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  • 51. Descheemaeker, K.A.
    et al.
    Nelles, L
    Strandberg, L
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Collen, D
    Transfection of human endothelial cells with human plasminogen activator inhibitor type-1 promoter-reporter gene fragmentes reveals phorbol ester induciton of gene expression1992In: Fibrinolysis, ISSN 0268-9499, Vol. 6, no 4, p. 256-262Article in journal (Refereed)
  • 52. Dethoff, Elizabeth A
    et al.
    Petzold, Katja
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chugh, Jeetender
    Casiano-Negroni, Anette
    Al-Hashimi, Hashim M
    Visualizing transient low-populated structures of RNA2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, p. 724-728Article in journal (Refereed)
    Abstract [en]

    The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 μs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.

  • 53.
    Djusberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lundberg, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases2017In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

  • 54. Do, Ron
    et al.
    Willer, Cristen J.
    Schmidt, Ellen M.
    Sengupta, Sebanti
    Gao, Chi
    Peloso, Gina M.
    Gustafsson, Stefan
    Kanoni, Stavroula
    Ganna, Andrea
    Chen, Jin
    Buchkovich, Martin L.
    Mora, Samia
    Beckmann, Jacques S.
    Bragg-Gresham, Jennifer L.
    Chang, Hsing-Yi
    Demirkan, Ayse
    Den Hertog, Heleen M.
    Donnelly, Louise A.
    Ehret, Georg B.
    Esko, Tonu
    Feitosa, Mary F.
    Ferreira, Teresa
    Fischer, Krista
    Fontanillas, Pierre
    Fraser, Ross M.
    Freitag, Daniel F.
    Gurdasani, Deepti
    Heikkila, Kauko
    Hyppoenen, Elina
    Isaacs, Aaron
    Jackson, Anne U.
    Johansson, Asa
    Johnson, Toby
    Kaakinen, Marika
    Kettunen, Johannes
    Kleber, Marcus E.
    Li, Xiaohui
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Magnusson, Patrik K. E.
    Mangino, Massimo
    Mihailov, Evelin
    Montasser, May E.
    Mueller-Nurasyid, Martina
    Nolte, Ilja M.
    O'Connell, Jeffrey R.
    Palmer, Cameron D.
    Perola, Markus
    Petersen, Ann-Kristin
    Sanna, Serena
    Saxena, Richa
    Service, Susan K.
    Shah, Sonia
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology. Lunds universitet.
    Sidore, Carlo
    Song, Ci
    Strawbridge, Rona J.
    Surakka, Ida
    Tanaka, Toshiko
    Teslovich, Tanya M.
    Thorleifsson, Gudmar
    Van den Herik, Evita G.
    Voight, Benjamin F.
    Volcik, Kelly A.
    Waite, Lindsay L.
    Wong, Andrew
    Wu, Ying
    Zhang, Weihua
    Absher, Devin
    Asiki, Gershim
    Barroso, Ines
    Been, Latonya F.
    Bolton, Jennifer L.
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Burnett, Mary S.
    Cesana, Giancarlo
    Dimitriou, Maria
    Doney, Alex S. F.
    Doering, Angela
    Elliott, Paul
    Epstein, Stephen E.
    Eyjolfsson, Gudmundur Ingi
    Gigante, Bruna
    Goodarzi, Mark O.
    Grallert, Harald
    Gravito, Martha L.
    Groves, Christopher J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Hernandez, Dena
    Hicks, Andrew A.
    Holm, Hilma
    Hung, Yi-Jen
    Illig, Thomas
    Jones, Michelle R.
    Kaleebu, Pontiano
    Kastelein, John J. P.
    Khaw, Kay-Tee
    Kim, Eric
    Klopp, Norman
    Komulainen, Pirjo
    Kumari, Meena
    Langenberg, Claudia
    Lehtimaki, Terho
    Lin, Shih-Yi
    Lindstrom, Jaana
    Loos, Ruth J. F.
    Mach, Francois
    McArdle, Wendy L.
    Meisinger, Christa
    Mitchell, Braxton D.
    Mueller, Gabrielle
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nieminen, Tuomo V. M.
    Nsubuga, Rebecca N.
    Olafsson, Isleifur
    Ong, Ken K.
    Palotie, Aarno
    Papamarkou, Theodore
    Pomilla, Cristina
    Pouta, Anneli
    Rader, Daniel J.
    Reilly, Muredach P.
    Ridker, Paul M.
    Rivadeneira, Fernando
    Rudan, Igor
    Ruokonen, Aimo
    Samani, Nilesh
    Scharnagl, Hubert
    Seeley, Janet
    Silander, Kaisa
    Stancakova, Alena
    Stirrups, Kathleen
    Swift, Amy J.
    Tiret, Laurence
    Uitterlinden, Andre G.
    van Pelt, L. Joost
    Vedantam, Sailaja
    Wainwright, Nicholas
    Wijmenga, Cisca
    Wild, Sarah H.
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wilson, James F.
    Young, Elizabeth H.
    Zhao, Jing Hua
    Adair, Linda S.
    Arveiler, Dominique
    Assimes, Themistocles L.
    Bandinelli, Stefania
    Bennett, Franklyn
    Bochud, Murielle
    Boehm, Bernhard O.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    Bornstein, Stefan R.
    Bovet, Pascal
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chambers, John C.
    Chen, Yii-Der Ida
    Collins, Francis S.
    Cooper, Richard S.
    Danesh, John
    Dedoussis, George
    de Faire, Ulf
    Feranil, Alan B.
    Ferrieres, Jean
    Ferrucci, Luigi
    Freimer, Nelson B.
    Gieger, Christian
    Groop, Leif C.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hamsten, Anders
    Harris, Tamara B.
    Hingorani, Aroon
    Hirschhorn, Joel N.
    Hofman, Albert
    Hovingh, G. Kees
    Hsiung, Chao Agnes
    Humphries, Steve E.
    Hunt, Steven C.
    Hveem, Kristian
    Iribarren, Carlos
    Jarvelin, Marjo-Riitta
    Jula, Antti
    Kahonen, Mika
    Kaprio, Jaakko
    Kesaniemi, Antero
    Kivimaki, Mika
    Kooner, Jaspal S.
    Koudstaal, Peter J.
    Krauss, Ronald M.
    Kuh, Diana
    Kuusisto, Johanna
    Kyvik, Kirsten O.
    Laakso, Markku
    Lakka, Timo A.
    Lind, Lars
    Lindgren, Cecilia M.
    Martin, Nicholas G.
    Maerz, Winfried
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Metspalu, Andres
    Moilanen, Leena
    Morris, Andrew D.
    Munroe, Patricia B.
    Njolstad, Inger
    Pedersen, Nancy L.
    Power, Chris
    Pramstaller, Peter P.
    Price, Jackie F.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rauramaa, Rainer
    Saleheen, Danish
    Salomaa, Veikko
    Sanghera, Dharambir K.
    Saramies, Jouko
    Schwarz, Peter E. H.
    Sheu, Wayne H-H
    Shuldiner, Alan R.
    Siegbahn, Agneta
    Spector, Tim D.
    Stefansson, Kari
    Strachan, David P.
    Tayo, Bamidele O.
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van Duijn, Cornelia M.
    Vollenweider, Peter
    Wallentin, Lars
    Wareham, Nicholas J.
    Whitfield, John B.
    Wolffenbuttel, Bruce H. R.
    Altshuler, David
    Ordovas, Jose M.
    Boerwinkle, Eric
    Palmer, Colin N. A.
    Thorsteinsdottir, Unnur
    Chasman, Daniel I.
    Rotter, Jerome I.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lunds universitet, Harvard University.
    Ripatti, Samuli
    Cupples, L. Adrienne
    Sandhu, Manjinder S.
    Rich, Stephen S.
    Boehnke, Michael
    Deloukas, Panos
    Mohlke, Karen L.
    Ingelsson, Erik
    Abecasis, Goncalo R.
    Daly, Mark J.
    Neale, Benjamin M.
    Kathiresan, Sekar
    Common variants associated with plasma triglycerides and risk for coronary artery disease2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 11, p. 1345-+Article in journal (Refereed)
    Abstract [en]

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

  • 55. Dudding, Tom
    et al.
    Haworth, Simon
    Lind, Penelope A.
    Sathirapongsasuti, J. Fah
    Tung, Joyce Y.
    Mitchell, Ruth
    Colodro-Conde, Lucia
    Medland, Sarah E.
    Gordon, Scott
    Elsworth, Benjamin
    Paternoster, Lavinia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Sweden ; Department of Nutrition, Harvard. Chan School of Public Health, Harvard University, Boston USA.
    Thomas, Steven J.
    Martin, Nicholas G.
    Timpson, Nicholas J.
    Agee, Michelle
    Alipanahi, Babak
    Auton, Adam
    Bell, Robert K.
    Bryc, Katarzyna
    Elson, Sarah L.
    Fontanillas, Pierre
    Furlotte, Nicholas A.
    Hicks, Barry
    Hinds, David A.
    Huber, Karen E.
    Jewett, Ethan M.
    Jiang, Yunxuan
    Kleinman, Aaron
    Lin, Keng-Han
    Litterman, Nadia K.
    McCeight, Jennifer C.
    McIntyre, Matthew H.
    McManus, Kimberly F.
    Mountain, Joanna L.
    Noblin, Elizabeth S.
    Northover, Carrie A. M.
    Pitts, Steven J.
    Poznik, David
    Shelton, Janie F.
    Shringarpure, Suyash
    Tian, Chao
    Vacic, Vladimir
    Wang, Xin
    Wilson, Catherine H.
    Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, p. 1-12, article id 1052Article in journal (Refereed)
    Abstract [en]

    Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

  • 56. Duell, Eric J
    et al.
    Lujan-Barroso, Leila
    Llivina, Claudia
    Muñoz, Xavier
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Boeing, Heiner
    Buijsse, Brian
    Canzian, Federico
    Johnson, Theron
    Dalgård, Christine
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Sánchez, Soledad C
    Sánchez-Cantalejo, Emilio
    Huerta, José-María
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Travis, Ruth C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Rafnsson, Snorri
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Grioni, Sara
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Numans, Mattijs E
    Peeters, Petra H
    Johansen, Dorthe
    Lindkvist, Björn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Skeie, Guri
    Weiderpass, Elisabete
    Duarte-Salles, Talita
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort2013In: Genes & Nutrition, ISSN 1555-8932, E-ISSN 1865-3499, Vol. 8, no 6, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.

  • 57. Dörr, Tobias
    et al.
    Lam, Hubert
    Alvarez, Laura
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Davis, Brigid M.
    Waldor, Matthew K.
    A novel peptidoglycan binding protein crucial for PBP1A-mediated cell wall biogenesis in Vibrio cholerae2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004433-Article in journal (Refereed)
    Abstract [en]

    The bacterial cell wall, which is comprised of a mesh of polysaccharide strands crosslinked via peptide bridges (peptidoglycan, PG), is critical for maintenance of cell shape and survival. PG assembly is mediated by a variety of Penicillin Binding Proteins (PBP) whose fundamental activities have been characterized in great detail; however, there is limited knowledge of the factors that modulate their activities in different environments or growth phases. In Vibrio cholerae, the cause of cholera, PG synthesis during the transition into stationary phase is primarily mediated by the bifunctional enzyme PBP1A. Here, we screened an ordered V. cholerae transposon library for mutants that are sensitive to growth inhibition by non-canonical D-amino acids (DAA), which prevent growth and maintenance of cell shape in PBP1A-deficient V. cholerae. In addition to PBP1A and its lipoprotein activator LpoA, we found that CsiV, a small periplasmic protein with no previously described function, is essential for growth in the presence of DAA. Deletion of csiV, like deletion of lpoA or the PBP1A-encoding gene mrcA, causes cells to lose their rod shape in the presence of DAA or the beta-lactam antibiotic cefsulodin, and all three mutations are synthetically lethal with deletion of mrcB, which encodes PBP1B, V. cholerae's second key bifunctional PBP. CsiV interacts with LpoA and PG but apparently not with PBP1A, supporting the hypothesis that CsiV promotes LpoA's role as an activator of PBP1A, and thereby modulates V. cholerae PG biogenesis. Finally, the requirement for CsiV in PBP1A-mediated growth of V. cholerae can be overcome either by augmenting PG synthesis or by reducing PG degradation, thereby highlighting the importance of balancing these two processes for bacterial survival.

  • 58. Ehret, Georg B.
    et al.
    Ferreira, Teresa
    Chasman, Daniel I.
    Jackson, Anne U.
    Schmidt, Ellen M.
    Johnson, Toby
    Thorleifsson, Gudmar
    Luan, Jian'an
    Donnelly, Louise A.
    Kanoni, Stavroula
    Petersen, Ann -Kristin
    Pihurl, Vasyl
    Strawbridge, Rona J.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Hughes, Maria F.
    Meirelles, Osorio
    Kaakinen, Marika
    Bouatia-Naji, Nabila
    Kristiansson, Kati
    Shah, Sonia
    Kleber, Marcus E.
    Guo, Xiuqing
    Lyytikainen, Leo-Pekka
    Fava, Cristiano
    Eriksson, Nidas
    Nolte, Ilja M.
    Magnusson, Patrik K.
    Salfati, Elias L.
    Rallidis, Loukianos S.
    Theusch, Elizabeth
    Smith, Andrew J. P.
    Folkersen, Lasse
    Witkowska, Kate
    Pers, Tune H.
    Joehanes, Roby
    Kim, Stuart K.
    Lataniotis, Lazaros
    Jansen, Rick
    Johnson, Andrew D.
    Warren, Helen
    Kim, Young Jin
    Zhao, Wei
    Wu, Ying
    Tayo, Bamidele O.
    Bochud, Murielle
    Absher, Devin
    Adair, Linda S.
    Amin, Najaf
    Arkingl, Dan E.
    Axelsson, Tomas
    Baldassarre, Damian
    Balkau, Beverley
    Bandinelli, Stefania
    Barnes, Michael R.
    Barroso, Ines
    Bevan, Stephen
    Bis, Joshua C.
    Bjornsdottir, Gyda
    Boehnke, Michael
    Boerwinkle, Eric
    Bonnycastle, Lori L.
    Boomsma, Dorret I.
    Bornstein, Stefan R.
    Brown, Morris J.
    Burnier, Michel
    Cabrera, Claudia P.
    Chambers, John C.
    Chang, I-Shou
    Cheng, Ching-Yu
    Chines, Peter S.
    Chung, Ren-Hua
    Collins, Francis S.
    Connell, John M.
    Doring, Angela
    Dallongeville, Jean
    Danesh, John
    de Faire, Ulf
    Delgado, Graciela
    Dominiczak, Anna F.
    Doney, Alex S. F.
    Drenos, Fotios
    Edkins, Sarah
    Eicher, John D.
    Elosua, Roberto
    Enroth, Stefan
    Erdmann, Jeanette
    Eriksson, Per
    Esko, Tonu
    Evangelou, Evangelos
    Evans, Alun
    Fai, Tove
    Farra, Martin
    Felixl, Janine F.
    Ferrieres, Jean
    Ferrucci, Luigi
    Fornage, Myriam
    Forrester, Terrence
    Franceschinil, Nora
    Franco, Oscar H.
    Franco-Cereceda, Anders
    Fraser, Ross M.
    Ganesh, Santhi K.
    Gao, He
    Gertow, Karl
    Gianfagna, Francesco
    Gigante, Bruna
    Giulianini, Franco
    Goe, Anuj
    Goodall, Alison H.
    Goodarzi, Mark
    Gorski, Mathias
    Grassler, Jurgen
    Groves, Christopher J.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hartikainen, Anna-Liisa
    Hassinen, Maija
    Havulinna, Aki S.
    Hayward, Caroline
    Hercberg, Serge
    Herzig, Karl-Heinz
    Hicks, Andrew A.
    Hingorani, Aroon D.
    Hirschhorn, Joel N.
    Hofmanl, Albert
    Holmen, Jostein
    Holmen, Oddgeir Lingaas
    Hottenga, Jouke-Jan
    Howard, Phil
    Hsiung, Chao A.
    Hunt, Steven C.
    Ikram, M. Arfan
    Illig, Thomas
    Iribarren, Carlos
    Jensen, Richard A.
    Kahonen, Mika
    Kang, Hyun Min
    Kathiresan, Sekar
    Keating, Brendan J.
    Khaw, Kay-Tee
    Kim, Yun Kyoung
    Kim, Eric
    Kivimaki, Mika
    Klopp, Norman
    Kolovou, Genovefa
    Komulainen, Pirjo
    Kooner, Jaspal S.
    Kosova, Gulum
    Krauss, Ronald M.
    Kuh, Diana
    Kutalik, Zoltan
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Lakka, Timo A.
    Lee, Nanette R.
    Lee, I-Te
    Lee, Wen-Jane
    Levy, Daniel
    Li, Xiaohui
    Liang, Kae-Woei
    Lin, Honghuang
    Lin, Li
    Lindstrom, Jaana
    Lobbens, Stephane
    Mannisto, Satu
    Muller, Gabriele
    Muller-Nurasyid, Martina
    Mach, Francois
    Markus, Hugh S.
    Marouli, Eirini
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Menni, Cristina
    Metspalu, Andres
    Mijatovic, Vladan
    Moilanen, Leena
    Montasser, May E.
    Morris, Andrew D.
    Morrison, Alanna C.
    Mulas, Antonella
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nikus, Kjell
    O'Donnell, Christopher J.
    O'Reilly, Paul F.
    Ong, Ken K.
    Paccaud, Fred
    Palmer, Cameron D.
    Parsa, Afshin
    Pedersen, Nancy L.
    Penninx, Brenda W.
    Perola, Markus
    Peters, Annette
    Poulter, Neil
    Pramstaller, Peter P.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rao, Dabeeru C.
    Rasheed, Asif
    Rayner, N. William
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rettig, Rainer
    Rice, Kenneth M.
    Roberts, Robert
    Rose, Lynda M.
    Rossouw, Jacques
    Samani, Nilesh J.
    Sanna, Serena
    Saramies, Jouko
    Schunkert, Heribert
    Sebert, Sylvain
    Sheu, Wayne H-H
    Shin, Young-Ah
    Sim, Xueling
    Smit, Johannes H.
    Smith, Albert V.
    Sosa, Maria X.
    Spector, Tim D.
    Stancakova, Alena
    Stanton, Alice V.
    Stirrups, Kathleen E.
    Stringham, Heather M.
    Sundstrom, Johan
    Swift, Amy J.
    Syvanen, Ann-Christine
    Tai, E-Shyong
    Tanaka, Toshiko
    Tarasov, Kirill V.
    Teumer, Alexander
    Thorsteinsdottir, Unnur
    Tobin, Martin D.
    Tremoli, Elena
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Vaez, Ahmad
    Vaidya, Dhananjay
    van Duijn, Cornelia M.
    van Iperen, Erik P. A.
    Vasan, Ramachandran S.
    Verwoert, Germaine C.
    Virtamo, Jarmo
    Vitart, Veronique
    Voight, Benjamin F.
    Vollenweider, Peter
    Wagner, Aline
    Wain, Louise V.
    Wareham, Nicholas J.
    Watldns, Hugh
    Weder, Alan B.
    Westra, Harm Jan
    Wilks, Rainford
    Wilsgaard, Tom
    Wilson, James F.
    Wong, Tien Y.
    Yang, Tsun-Po
    Yao, Jie
    Yengo, Loic
    Zhang, Weihua
    Zhao, Jing Hua
    Zhu, Xiaofeng
    Bovet, Pascal
    Cooper, Richard S.
    Mohlke, Karen L.
    Saleheen, Danish
    Lee, Jong-Young
    Elliott, Paul
    Gierman, Hinco J.
    Willer, Cristen J.
    Franke, Lude
    Hovingh, G. Kees
    Taylor, Kent D.
    Dedoussis, George
    Sever, Peter
    Wong, Andrew
    Lind, Lars
    Assimes, Themistocles L.
    Njolstad, Inger
    Schwarz, Peter E. H.
    Langenberg, Claudia
    Snieder, Harold
    Caulfield, Mark J.
    Melander, E.
    Laakso, Markku
    Saltevo, Juha
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Ingelsson, Erik
    Lehtimaki, Terho
    Hveem, Kristian
    Palmas, Walter
    Marz, Winfried
    Kumar, Meena
    Salomaa, Veikko
    Chen, Yii-Der I.
    Rotter, Jerome I.
    Froguel, Philippe
    Jarvelin, Marjo-Riitta
    Lakatta, Edward G.
    Kuulasmaa, Kari
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
    Hamsten, Anders
    Wichmann, H-Erich
    Palmer, Colin N. A.
    Stefansson, Kari
    Ridker, Paul M.
    Loos, Ruth J. F.
    Chalcravarti, Aravinda
    Deloukas, Panos
    Morris, Andrew P.
    Newton-Cheh, Christopher
    Munroe, Patricia B.
    The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 10, p. 1171-1184Article in journal (Refereed)
    Abstract [en]

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

  • 59.
    Einarsdottir, Elisabet
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Mapping genetic diseases in northern Sweden2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.

  • 60.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Ruikka, Karin
    Andersson Escher, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Näringsforskning.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden2006In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 6, p. 1879-1883Article in journal (Refereed)
  • 61.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, p. 81-84Article in journal (Refereed)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 62. Ek, Weronica E.
    et al.
    Tobi, Elmar W.
    Ahsan, Muhammad
    Lampa, Erik
    Ponzi, Erica
    Kyrtopoulos, Soterios A.
    Georgiadis, Panagiotis
    Lumey, L. H.
    Heijmans, Bastiaan T.
    Botsivali, Maria
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Karlsson, Torgny
    Rask-Andersen, Mathias
    Palli, Domenico
    Ingelsson, Erik
    Hedman, Åsa K.
    Nilsson, Lena M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vineis, Paolo
    Lind, Lars
    Flanagan, James M.
    Johansson, Åsa
    Tea and coffee consumption in relation to DNA methylation in four European cohorts2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 16, p. 3221-3231Article in journal (Refereed)
    Abstract [en]

    Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

  • 63.
    Elfving, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chereji, Razvan V.
    Bharatula, Vasudha
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Morozov, Alexandre V.
    Broach, James R.
    A dynamic interplay of nucleosome and Msn2 binding regulates kinetics of gene activation and repression following stress2014In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 9, p. 5468-5482Article in journal (Refereed)
    Abstract [en]

    The transcription factor Msn2 mediates a significant proportion of the environmental stress response, in which a common cohort of genes changes expression in a stereotypic fashion upon exposure to any of a wide variety of stresses. We have applied genome-wide chromatin immunoprecipitation and nucleosome profiling to determine where Msn2 binds under stressful conditions and how that binding affects, and is affected by, nucleosome positioning. We concurrently determined the effect of Msn2 activity on gene expression following stress and demonstrated that Msn2 stimulates both activation and repression. We found that some genes responded to both intermittent and continuous Msn2 nuclear occupancy while others responded only to continuous occupancy. Finally, these studies document a dynamic interplay between nucleosomes and Msn2 such that nucleosomes can restrict access of Msn2 to its canonical binding sites while Msn2 can promote reposition, expulsion and recruitment of nucleosomes to alter gene expression. This interplay may allow the cell to discriminate between different types of stress signaling.

  • 64. Erzurumluoglu, A Mesut
    et al.
    Liu, Mengzhen
    Jackson, Victoria E
    Barnes, Daniel R
    Datta, Gargi
    Melbourne, Carl A
    Young, Robin
    Batini, Chiara
    Surendran, Praveen
    Jiang, Tao
    Adnan, Sheikh Daud
    Afaq, Saima
    Agrawal, Arpana
    Altmaier, Elisabeth
    Antoniou, Antonis C
    Asselbergs, Folkert W
    Baumbach, Clemens
    Bierut, Laura
    Bertelsen, Sarah
    Boehnke, Michael
    Bots, Michiel L
    Brazel, David M
    Chambers, John C
    Chang-Claude, Jenny
    Chen, Chu
    Corley, Janie
    Chou, Yi-Ling
    David, Sean P
    de Boer, Rudolf A
    de Leeuw, Christiaan A
    Dennis, Joe G
    Dominiczak, Anna F
    Dunning, Alison M
    Easton, Douglas F
    Eaton, Charles
    Elliott, Paul
    Evangelou, Evangelos
    Faul, Jessica D
    Foroud, Tatiana
    Goate, Alison
    Gong, Jian
    Grabe, Hans J
    Haessler, Jeff
    Haiman, Christopher
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hammerschlag, Anke R
    Harris, Sarah E
    Hattersley, Andrew
    Heath, Andrew
    Hsu, Chris
    Iacono, William G
    Kanoni, Stavroula
    Kapoor, Manav
    Kaprio, Jaakko
    Kardia, Sharon L
    Karpe, Fredrik
    Kontto, Jukka
    Kooner, Jaspal S
    Kooperberg, Charles
    Kuulasmaa, Kari
    Laakso, Markku
    Lai, Dongbing
    Langenberg, Claudia
    Le, Nhung
    Lettre, Guillaume
    Loukola, Anu
    Luan, Jian'an
    Madden, Pamela A F
    Mangino, Massimo
    Marioni, Riccardo E
    Marouli, Eirini
    Marten, Jonathan
    Martin, Nicholas G
    McGue, Matt
    Michailidou, Kyriaki
    Mihailov, Evelin
    Moayyeri, Alireza
    Moitry, Marie
    Müller-Nurasyid, Martina
    Naheed, Aliya
    Nauck, Matthias
    Neville, Matthew J
    Nielsen, Sune Fallgaard
    North, Kari
    Perola, Markus
    Pharoah, Paul D P
    Pistis, Giorgio
    Polderman, Tinca J
    Posthuma, Danielle
    Poulter, Neil
    Qaiser, Beenish
    Rasheed, Asif
    Reiner, Alex
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Lund University.
    Rice, John
    Rohde, Rebecca
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Samani, Nilesh J
    Samuel, Maria
    Schlessinger, David
    Scholte, Steven H
    Scott, Robert A
    Sever, Peter
    Shao, Yaming
    Shrine, Nick
    Smith, Jennifer A
    Starr, John M
    Stirrups, Kathleen
    Stram, Danielle
    Stringham, Heather M
    Tachmazidou, Ioanna
    Tardif, Jean-Claude
    Thompson, Deborah J
    Tindle, Hilary A
    Tragante, Vinicius
    Trompet, Stella
    Turcot, Valerie
    Tyrrell, Jessica
    Vaartjes, Ilonca
    van der Leij, Andries R
    van der Meer, Peter
    Varga, Tibor V
    Verweij, Niek
    Völzke, Henry
    Wareham, Nicholas J
    Warren, Helen R
    Weir, David R
    Weiss, Stefan
    Wetherill, Leah
    Yaghootkar, Hanieh
    Yavas, Ersin
    Jiang, Yu
    Chen, Fang
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Wei
    Zhao, Wei
    Zhou, Kaixin
    Amouyel, Philippe
    Blankenberg, Stefan
    Caulfield, Mark J
    Chowdhury, Rajiv
    Cucca, Francesco
    Deary, Ian J
    Deloukas, Panos
    Di Angelantonio, Emanuele
    Ferrario, Marco
    Ferrières, Jean
    Franks, Paul W
    Frayling, Tim M
    Frossard, Philippe
    Hall, Ian P
    Hayward, Caroline
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden..
    Jukema, J Wouter
    Kee, Frank
    Männistö, Satu
    Metspalu, Andres
    Munroe, Patricia B
    Nordestgaard, Børge Grønne
    Palmer, Colin N A
    Salomaa, Veikko
    Sattar, Naveed
    Spector, Timothy
    Strachan, David Peter
    van der Harst, Pim
    Zeggini, Eleftheria
    Saleheen, Danish
    Butterworth, Adam S
    Wain, Louise V
    Abecasis, Goncalo R
    Danesh, John
    Tobin, Martin D
    Vrieze, Scott
    Liu, Dajiang J
    Howson, Joanna M M
    Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci2019In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed)
    Abstract [en]

    Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

  • 65.
    Eschbach, Judith
    et al.
    Neurology, Ulm University, Germany.
    Schwalenstocker, Birgit
    Neurology, Ulm University, Germany.
    Soyal, Selma M.
    Pharmacology, Paracelsus Medical University, Salzburg, Austria.
    Bayer, Hanna
    Neurology, Ulm University, Germany.
    Wiesner, Diana
    Neurology, Ulm University, Germany.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Meyer, Thomas
    Neurology, Charité University Hospital, Berlin, Germany.
    Dupuis, Luc
    INSERM, Strasbourg, France ; Faculté de Médecine, Université de Strasbourg, , France.
    Danzer, Karin M.
    Neurology, Ulm University, Germany.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Neurology, Ulm University, Germany.
    Witting, Anke
    Neurology, Ulm University, Germany.
    Ludolph, Albert C.
    Neurology, Ulm University, Germany.
    Patsch, Wolfgang
    Pharmacology, Paracelsus Medical University, Salzburg, Austria.
    Weydt, Patrick
    Neurology, Ulm University, Germany.
    PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis2013In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 17, p. 3477-3484Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.

  • 66. Espín-Pérez, Almudena
    et al.
    Hebels, Dennie G. A. J.
    Kiviranta, Hannu
    Rantakokko, Panu
    Georgiadis, Panagiotis
    Botsivali, Maria
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Palli, Domenico
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Chadeau-Hyam, Marc
    Kyrtopoulos, Soterios A
    Kleinjans, Jos C. S.
    de Kok, Theo M. C. M.
    Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs)2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 746Article in journal (Refereed)
    Abstract [en]

    PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.

  • 67. Estrada, Karol
    et al.
    Styrkarsdottir, Unnur
    Evangelou, Evangelos
    Hsu, Yi-Hsiang
    Duncan, Emma L
    Ntzani, Evangelia E
    Oei, Ling
    Albagha, Omar ME
    Amin, Najaf
    Kemp, John P
    Koller, Daniel L
    Li, Guo
    Liu, Ching-Ti
    Minster, Ryan L
    Moayyeri, Alireza
    Vandenput, Liesbeth
    Willner, Dana
    Xiao, Su-Mei
    Yerges-Armstrong, Laura M
    Zheng, Hou-Feng
    Alonso, Nerea
    Eriksson, Joel
    Kammerer, Candace M
    Kaptoge, Stephen K
    Leo, Paul J
    Thorleifsson, Gudmar
    Wilson, Scott G
    Wilson, James F
    Aalto, Ville
    Alen, Markku
    Aragaki, Aaron K
    Aspelund, Thor
    Center, Jacqueline R
    Dailiana, Zoe
    Duggan, David J
    Garcia, Melissa
    Garcia-Giralt, Natàlia
    Giroux, Sylvie
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hocking, Lynne J
    Husted, Lise Bjerre
    Jameson, Karen A
    Khusainova, Rita
    Kim, Ghi Su
    Kooperberg, Charles
    Koromila, Theodora
    Kruk, Marcin
    Laaksonen, Marika
    Lacroix, Andrea Z
    Lee, Seung Hun
    Leung, Ping C
    Lewis, Joshua R
    Masi, Laura
    Mencej-Bedrac, Simona
    Nguyen, Tuan V
    Nogues, Xavier
    Patel, Millan S
    Prezelj, Janez
    Rose, Lynda M
    Scollen, Serena
    Siggeirsdottir, Kristin
    Smith, Albert V
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Trompet, Stella
    Trummer, Olivia
    van Schoor, Natasja M
    Woo, Jean
    Zhu, Kun
    Balcells, Susana
    Brandi, Maria Luisa
    Buckley, Brendan M
    Cheng, Sulin
    Christiansen, Claus
    Cooper, Cyrus
    Dedoussis, George
    Ford, Ian
    Frost, Morten
    Goltzman, David
    González-Macías, Jesús
    Kähönen, Mika
    Karlsson, Magnus
    Khusnutdinova, Elza
    Koh, Jung-Min
    Kollia, Panagoula
    Langdahl, Bente Lomholt
    Leslie, William D
    Lips, Paul
    Ljunggren, Osten
    Lorenc, Roman S
    Marc, Janja
    Mellström, Dan
    Obermayer-Pietsch, Barbara
    Olmos, José M
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Reid, David M
    Riancho, José A
    Ridker, Paul M
    Rousseau, François
    Lagboom, P Eline S
    Tang, Nelson LS
    Urreizti, Roser
    Van Hul, Wim
    Viikari, Jorma
    Zarrabeitia, María T
    Aulchenko, Yurii S
    Castano-Betancourt, Martha
    Grundberg, Elin
    Herrera, Lizbeth
    Ingvarsson, Thorvaldur
    Johannsdottir, Hrefna
    Kwan, Tony
    Li, Rui
    Luben, Robert
    Medina-Gómez, Carolina
    Th Palsson, Stefan
    Reppe, Sjur
    Rotter, Jerome I
    Sigurdsson, Gunnar
    van Meurs, Joyce BJ
    Verlaan, Dominique
    Williams, Frances MK
    Wood, Andrew R
    Zhou, Yanhua
    Gautvik, Kaare M
    Pastinen, Tomi
    Raychaudhuri, Soumya
    Cauley, Jane A
    Chasman, Daniel I
    Clark, Graeme R
    Cummings, Steven R
    Danoy, Patrick
    Dennison, Elaine M
    Eastell, Richard
    Eisman, John A
    Gudnason, Vilmundur
    Hofman, Albert
    Jackson, Rebecca D
    Jones, Graeme
    Jukema, J Wouter
    Khaw, Kay-Tee
    Lehtimäki, Terho
    Liu, Yongmei
    Lorentzon, Mattias
    McCloskey, Eugene
    Mitchell, Braxton D
    Nandakumar, Kannabiran
    Nicholson, Geoffrey C
    Oostra, Ben A
    Peacock, Munro
    Pols, Huibert AP
    Prince, Richard L
    Raitakari, Olli
    Reid, Ian R
    Robbins, John
    Sambrook, Philip N
    Sham, Pak Chung
    Shuldiner, Alan R
    Tylavsky, Frances A
    van Duijn, Cornelia M
    Wareham, Nick J
    Cupples, L Adrienne
    Econs, Michael J
    Evans, David M
    Harris, Tamara B
    Kung, Annie Wai Chee
    Psaty, Bruce M
    Reeve, Jonathan
    Spector, Timothy D
    Streeten, Elizabeth A
    Zillikens, M Carola
    Thorsteinsdottir, Unnur
    Ohlsson, Claes
    Karasik, David
    Richards, J Brent
    Brown, Matthew A
    Stefansson, Kari
    Uitterlinden, André G
    Ralston, Stuart H
    Ioannidis, John PA
    Kiel, Douglas P
    Rivadeneira, Fernando
    Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, p. 491-501Article in journal (Refereed)
    Abstract [en]

    Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

  • 68. Farias, Fabiana H. G.
    et al.
    Dahlqvist, Johanna
    Kozyrev, Sergey V.
    Leonard, Dag
    Wilbe, Maria
    Abramov, Sergei N.
    Alexsson, Andrei
    Pielberg, Gerli R.
    Hansson-Hamlin, Helene
    Andersson, Goran
    Tandre, Karolina
    Bengtsson, Anders A.
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Syvanen, Ann-Christine
    Sandling, Johanna K.
    Eloranta, Maija-Leena
    Rönnblom, Lars
    Lindblad-Toh, Kerstin
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 432-441Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted resequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0 .014 , CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-Ul-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

  • 69. Farkas, Sanja A.
    et al.
    Vymetalkova, Veronika
    Vodickova, Ludmila
    Vodicka, Pavel
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes2014In: Epigenomics, ISSN 1750-1911, Vol. 6, no 2, p. 179-191Article in journal (Refereed)
    Abstract [en]

    Aim: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway. Material & methods: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip. Results: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes. Conclusion: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.

  • 70. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 10192Article in journal (Refereed)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

  • 71. Feitosa, Mary F.
    et al.
    Kraja, Aldi T.
    Chasman, Daniel I.
    Sung, Yun J.
    Winkler, Thomas W.
    Ntalla, Ioanna
    Guo, Xiuqing
    Franceschini, Nora
    Cheng, Ching-Yu
    Sim, Xueling
    Vojinovic, Dina
    Marten, Jonathan
    Musani, Solomon K.
    Li, Changwei
    Bentley, Amy R.
    Brown, Michael R.
    Schwander, Karen
    Richard, Melissa A.
    Noordam, Raymond
    Aschard, Hugues
    Bartz, Traci M.
    Bielak, Lawrence F.
    Dorajoo, Rajkumar
    Fisher, Virginia
    Hartwig, Fernando P.
    Horimoto, Andrea R. V. R.
    Lohman, Kurt K.
    Manning, Alisa K.
    Rankinen, Tuomo
    Smith, Albert V.
    Tajuddin, Salman M.
    Wojczynski, Mary K.
    Alver, Maris
    Boissel, Mathilde
    Cai, Qiuyin
    Campbell, Archie
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Gao, Chuan
    Goel, Anuj
    Hagemeijer, Yanick
    Harris, Sarah E.
    He, Meian
    Hsu, Fang-Chi
    Jackson, Anne U.
    Kahonen, Mika
    Kasturiratne, Anuradhani
    Komulainen, Pirjo
    Kuhnel, Brigitte
    Laguzzi, Federica
    Luan, Jian'an
    Matoba, Nana
    Nolte, Ilja M.
    Padmanabhan, Sandosh
    Riaz, Muhammad
    Rueedi, Rico
    Robino, Antonietta
    Said, M. Abdullah
    Scott, Robert A.
    Sofer, Tamar
    Stancakova, Alena
    Takeuchi, Fumihiko
    Tayo, Bamidele O.
    van der Most, Peter J.
    Varga, Tibor V.
    Vitart, Veronique
    Wang, Yajuan
    Ware, Erin B.
    Warren, Helen R.
    Weiss, Stefan
    Wen, Wanqing
    Yanek, Lisa R.
    Zhang, Weihua
    Zhao, Jing Hua
    Afaq, Saima
    Amin, Najaf
    Amini, Marzyeh
    Arking, Dan E.
    Aung, Tin
    Boerwinkle, Eric
    Borecki, Ingrid
    Broeckel, Ulrich
    Brown, Morris
    Brumat, Marco
    Burke, Gregory L.
    Canouil, Mickael
    Chakravarti, Aravinda
    Charumathi, Sabanayagam
    Chen, Yii-Der Ida
    Connell, John M.
    Correa, Adolfo
    Fuentes, Lisa de las
    de Mutsert, Renee
    de Silva, H. Janaka
    Deng, Xuan
    Ding, Jingzhong
    Duan, Qing
    Eaton, Charles B.
    Ehret, Georg
    Eppinga, Ruben N.
    Evangelou, Evangelos
    Fau, Jessica D.
    Felix, Stephan B.
    Forouhi, Nita G.
    Forrester, Terrence
    Franco, Oscar H.
    Friedlander, Yechiel
    Gandin, Ilaria
    Gao, He
    Ghanbari, Mohsen
    Gigante, Bruna
    Gu, C. Charles
    Gu, Dongfeng
    Hagenaars, Saskia P.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hirata, Makoto
    Howard, Barbara V.
    Ikram, M. Arfan
    John, Ulrich
    Katsuya, Tomohiro
    Khor, Chiea Chuen
    Kilpelainen, Tuomas O.
    Koh, Woon-Puay
    Krieger, Jose E.
    Kritchevsky, Stephen B.
    Kubo, Michiaki
    Kuusisto, Johanna
    Lakka, Timo A.
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Lehne, Benjamin
    Lewis, Cora E.
    Li, Yize
    Lin, Shiow
    Liu, Jianjun
    Liu, Jingmin
    Loh, Marie
    Louie, Tin
    Magi, Reedik
    McKenzie, Colin A.
    Meitinger, Thomas
    Metspalu, Andres
    Milaneschi, Yuri
    Milani, Lili
    Mohlke, Karen L.
    Momozawa, Yukihide
    Nalls, Mike A.
    Nelson, Christopher P.
    Sotoodehnia, NelsonNona
    Norris, Jill M.
    O'Connell, Jeff R.
    Palmer, Nicholette D.
    Perls, Thomas
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Poulter, Neil
    Raffel, Leslie J.
    Raitakari, Olli T.
    Roll, Kathryn
    Rose, Lynda M.
    Rosendaal, Frits R.
    Rotter, Jerome I.
    Schmidt, Carsten O.
    Schreiner, Pamela J.
    Schupf, Nicole
    Scott, William R.
    Sever, Peter S.
    Shi, Yuan
    Sidney, Stephen
    Sims, Mario
    Sitlani, Colleen M.
    Smith, Jennifer A.
    Snieder, Harold
    Starr, John M.
    Strauch, Konstantin
    Stringham, Heather M.
    Tan, Nicholas Y. Q.
    Tang, Hua
    Taylor, Kent D.
    Teo, Yik Ying
    Tham, Yih Chung
    Turner, Stephen T.
    Uitterlinden, Andre G.
    Vollenweider, Peter
    Waldenberger, Melanie
    Wang, Lihua
    Wang, Ya Xing
    Bin Wei, Wen
    Williams, Christine
    Yao, Jie
    Yu, Caizheng
    Yuan, Jian-Min
    Zhao, Wei
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    Chambers, John C.
    Deary, Ian J.
    Esko, Tonu
    Farrall, Martin
    Franks, Paul W.
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Jonas, Jost Bruno
    Kamatani, Yoichiro
    Kato, Norihiro
    Kooner, Jaspal S.
    Kutalik, Zoltan
    Laakso, Markku
    Laurie, Cathy C.
    Leander, Karin
    Lehtimaki, Terho
    Study, Lifelines Cohort
    Magnusson, Patrik K. E.
    Oldehinkel, Albertine J.
    Penninx, Brenda W. J. H.
    Poiasek, Ozren
    Porteous, David J.
    Rauramaa, Rainer
    Samani, Nilesh J.
    Scott, James
    Shu, Xiao-Ou
    van der Harst, Pim
    Wagenknecht, Lynne E.
    Wareham, Nicholas J.
    Watkins, Hugh
    Weir, David R.
    Wickremasinghe, Ananda R.
    Wu, Tangchun
    Zheng, Wei
    Bouchard, Claude
    Christensen, Kaare
    Evans, Michele K.
    Gudnason, Vilmundur
    Horta, Bernardo L.
    Kardia, Sharon L. R.
    Liu, Yongmei
    Pereira, Alexandre C.
    Psaty, Bruce M.
    Ridker, Paul M.
    van Dam, Rob M.
    Gauderman, W. James
    Zhu, Xiaofeng
    Mook-Kanamori, Dennis O.
    Fornage, Myriam
    Rotimi, Charles N.
    Cupples, L. Adrienne
    Kelly, Tanika N.
    Fox, Ervin R.
    Hayward, Caroline
    van Duijn, Cornelia M.
    Tai, E. Shyong
    Wong, Tien Yin
    Kooperberg, Charles
    Palmas, Walter
    Rice, Kenneth
    Morrison, Alanna C.
    Elliott, Paul
    Caulfield, Mark J.
    Munroe, Patricia B.
    Rao, Dabeeru C.
    Province, Michael A.
    Levy, Daniel
    Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0198166Article in journal (Refereed)
    Abstract [en]

    Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

  • 72. Ferreiro-Iglesias, Aida
    et al.
    Lesseur, Corina
    McKay, James
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Christiani, David
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Caporaso, Neil
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Kontic, Milica
    Ognjanovic, Simona
    Lissowska, Jolanta
    Szolkowska, Malgorzata
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Bolca, Ciprian
    Savic, Milan
    Ognjanovic, Miodrag
    Bojesen, Stig Egil
    Wu, Xifeng
    Albanes, Demetrios
    Aldrich, Melinda C.
    Tardon, Adonina
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    Le Marchand, Loic
    Rennert, Gadi
    Chen, Chu
    Doherty, Jennifer
    Goodman, Gary
    Bickeboeller, Heike
    Wichmann, H-Erich
    Risch, Angela
    Rosenberger, Albert
    Shen, Hongbing
    Dai, Juncheng
    Field, John K.
    Davies, Michael
    Woll, Penella
    Teare, M. Dawn
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Yuan, Jian-Min
    Hong, Yun-Chul
    Haugen, Aage
    Zienolddiny, Shanbeh
    Lam, Stephen
    Tsao, Ming-Sound
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Schabath, Matthew B.
    Andrew, Angeline
    Duell, Eric
    Melander, Olle
    Brunnstrom, Hans
    Lazarus, Philip
    Arnold, Susanne
    Slone, Stacey
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Landi, Maria Teresa
    Amos, Christopher, I
    Brennan, Paul
    Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 3927Article in journal (Refereed)
    Abstract [en]

    Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

  • 73. Figueroa, Jonine D.
    et al.
    Middlebrooks, Candace D.
    Banday, A. Rouf
    Ye, Yuanqing
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Koutros, Stella
    Kiemeney, Lambertus A.
    Rafnar, Thorunn
    Bishop, Timothy
    Furberg, Helena
    Matullo, Giuseppe
    Golka, Klaus
    Gago-Dominguez, Manuela
    Taylor, Jack A.
    Fletcher, Tony
    Siddiq, Afshan
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark P.
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Chung, Charles C.
    Vermeulen, Sita H.
    Aben, Katja K.
    Galesloot, Tessel E.
    Thorleifsson, Gudmar
    Sulem, Patrick
    Stefansson, Kari
    Kiltie, Anne E.
    Harland, Mark
    Teo, Mark
    Offit, Kenneth
    Vijai, Joseph
    Bajorin, Dean
    Kopp, Ryan
    Fiorito, Giovanni
    Guarrera, Simonetta
    Sacerdote, Carlotta
    Selinski, Silvia
    Hengstler, Jan G.
    Gerullis, Holger
    Ovsiannikov, Daniel
    Blaszkewicz, Meinolf
    Esteban Castelao, Jose
    Calaza, Manuel
    Martinez, Maria Elena
    Cordeiro, Patricia
    Xu, Zongli
    Panduri, Vijayalakshmi
    Kumar, Rajiv
    Gurzau, Eugene
    Koppova, Kvetoslava
    Bueno-De-Mesquita, H. Bas
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Francoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth C.
    Tjonneland, Anne
    Brennan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Stern, Marianna C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Jeppson, Rebecca P.
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Turman, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Zhang, Liren
    Gong, Yilei
    Pu, Xia
    Hutchinson, Amy
    Burdett, Laurie
    Wheeler, William A.
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Hosain, G. M. Monawar
    Schwenn, Molly
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie
    Virtamo, Jarmo
    Haiman, Christopher A.
    Landi, Maria Teresa
    Caporaso, Neil E.
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Chanock, Stephen J.
    Silverman, Debra T.
    Prokunina-Olsson, Ludmila
    Rothman, Nathaniel
    Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 6, p. 1203-1214Article in journal (Refereed)
    Abstract [en]

    Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

  • 74. Figueroa, Jonine D.
    et al.
    Ye, Yuanqing
    Siddiq, Afshan
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Prokunina-Olsson, Ludmila
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Tang, Wei
    Bueno-De-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Frangoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth
    Tjonneland, Anne
    Brenan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Rodabough, Rebecca
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Chen, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Lerner, Seth P.
    Grossman, H. Barton
    Lin, Jie
    Gu, Jian
    Pu, Xia
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Schwenn, Molly
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Armenti, Karla R.
    Hosain, G. M.
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Haiman, Chris A.
    Landi, Maria T.
    Caporaso, Neil
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Silverman, Debra T.
    Chanock, Stephen
    Rothman, Nathaniel
    Genome-wide association study identifies multiple loci associated with bladder cancer risk2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 5, p. 1387-1398Article in journal (Refereed)
    Abstract [en]

    andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

  • 75.
    Fischer, M Dominik
    et al.
    University of Pennsylvania School of Medicine.
    Gorospe, J Rafael
    George Washington University, Washington.
    Felder, Edward
    University of Pennsylvania School of Medicine, Philadelphia.
    Bogdanovich, Sasha
    University of Pennsylvania School of Medicine.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ahima, Rexford S
    University of Pennsylvania School of Medicine, Philadelphia.
    Rubinstein, Neal A
    University of Pennsylvania School of Medicine, Philadelphia.
    Hoffman, Eric P
    George Washington University, Washington.
    Khurana, Tejvir S
    University of Pennsylvania School of Medicine.
    Expression profiling reveals metabolic and structural components of extraocular muscles2002In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 9, no 2, p. 71-84Article in journal (Refereed)
    Abstract [en]

    The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.

  • 76. Fonseca, Luis Vazquez
    et al.
    Doimo, Mara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Clinical Genetics Unit, Department of Women and Children's Health, IRP Città della Speranza, University of Padova, Padova, Italy.
    Calderan, Cristina
    Desbats, Maria Andrea
    Acosta, Manuel J.
    Cerqua, Cristina
    Cassina, Matteo
    Ashraf, Shazia
    Hildebrandt, Friedhelm
    Sartori, Geppo
    Navas, Placido
    Trevisson, Eva
    Salviati, Leonardo
    Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function2018In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 3, p. 406-414Article in journal (Refereed)
    Abstract [en]

    Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a Delta COQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype-phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits.

  • 77.
    Forslund, Josefin M. E.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pfeiffer, Annika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Stojkovič, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wanrooij, Pauline H.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The presence of rNTPs decreases the speed of mitochondrial DNA replication2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 3, article id e1007315Article in journal (Refereed)
    Abstract [en]

    Ribonucleotides (rNMPs) are frequently incorporated during replication or repair by DNA polymerases and failure to remove them leads to instability of nuclear DNA (nDNA). Conversely, rNMPs appear to be relatively well-tolerated in mitochondnal DNA (mtDNA), although the mechanisms behind the tolerance remain unclear. We here show that the human mitochondrial DNA polymerase gamma (Pol gamma) bypasses single rNMPs with an unprecedentedly high fidelity and efficiency. In addition, Pol gamma exhibits a strikingly low frequency of rNMP incorporation, a property, which we find is independent of its exonuclease activity. However, the physiological levels of free rNTPs partially inhibit DNA synthesis by Pol gamma and render the polymerase more sensitive to imbalanced dNTP pools. The characteristics of Pol gamma reported here could have implications for forms of rntDNA depletion syndrome (MDS) that are associated with imbalanced cellular dNTP pools. Our results show that at the rNTPidNIP ratios that are expected to prevail in such disease states, Pol gamma enters a polymerasetexonuclease idling mode that leads to mtDNA replication stalling. This could ultimately lead to mtDNA depletion and, consequently, to mitochondrial disease phenotypes such as those observed in MDS.

  • 78.
    Franks, Paul W.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Merino, Jordi
    Gene-lifestyle interplay in type 2 diabetes2018In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 50, p. 35-40Article, review/survey (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) is widespread, affecting the health of hundreds of millions worldwide. The disease results from the complex interplay of lifestyle factors acting on a backdrop of inherited DNA risk variants. Detecting and understanding biomarkers, whether genotypes or other downstream biological features that dictate a person's phenotypic response to different lifestyle exposures, may have tremendous utility in the prevention of T2D. Here, we explore (i) evidence of how human genetic adaptation to diverse local environments might interact with lifestyle factors in T2D, (ii) the key challenges facing the research area of gene x lifestyle interactions in T2D, and (iii) the solutions that might be pursued in future studies. Overall, many preliminary examples of such interactions exist, but none is sufficient to have a major impact on clinical decision making. Future studies, integrating genetics and other biological markers into regulatory networks, are likely to be necessary to facilitate the integration of genomics into lifestyle medicine in T2D.

  • 79.
    Franks, Paul W.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, United Kingdom; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA.
    Timpson, Nicholas J.
    Genotype-Based Recall Studies in Complex Cardiometabolic Traits2018In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 11, no 8, article id e001947Article, review/survey (Refereed)
    Abstract [en]

    In genotype-based recall (GBR) studies, people (or their biological samples) who carry genotypes of special interest for a given hypothesis test are recalled from a larger cohort (or biobank) for more detailed investigations. There are several GBR study designs that offer a range of powerful options to elucidate (1) genotype-phenotype associations (by increasing the efficiency of genetic association studies, thereby allowing bespoke phenotyping in relatively small cohorts), (2) the effects of environmental exposures (within the Mendelian randomization framework), and (3) gene-treatment interactions (within the setting of GBR interventional trials). In this review, we overview the literature on GBR studies as applied to cardiometabolic health outcomes. We also review the GBR approaches used to date and outline new methods and study designs that might enhance the utility of GBR-focused studies. Specifically, we highlight how GBR methods have the potential to augment randomized controlled trials, providing an alternative application for the now increasingly accepted Mendelian randomization methods usually applied to large-scale population-based data sets. Further to this, we consider how functional and basic science approaches alongside GBR designs offer intellectually intriguing and potentially powerful ways to explore the implications of alterations to specific (and potentially druggable) biological pathways.

  • 80. Fransson, Susanne
    et al.
    Hansson, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Univ Gothenburg, Sahlgrenska Acad, Dept Pathol, SE-40530 Gothenburg, Sweden.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Djos, Anna
    Berbegall, Ana
    Javanmardi, Niloufar
    Abrahamsson, Jonas
    Palmer, Ruth H.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Univ Gothenburg, Sahlgrenska Acad, Dept Med Chem & Cell Biol, SE-40530 Gothenburg, Sweden.
    Noguera, Rosa
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Univ Gothenburg, Sahlgrenska Acad, Dept Med Chem & Cell Biol, SE-40530 Gothenburg, Sweden.
    Kogner, Per
    Martinsson, Tommy
    Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors2015In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 2, p. 99-109Article in journal (Refereed)
    Abstract [en]

    Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis. 

  • 81. Fuchsberger, Christian
    et al.
    Flannick, Jason
    Teslovich, Tanya M.
    Mahajan, Anubha
    Agarwala, Vineeta
    Gaulton, Kyle J.
    Ma, Clement
    Fontanillas, Pierre
    Moutsianas, Loukas
    McCarthy, Davis J.
    Rivas, Manuel A.
    Perry, John R. B.
    Sim, Xueling
    Blackwell, Thomas W.
    Robertson, Neil R.
    Rayner, N. William
    Cingolani, Pablo
    Locke, Adam E.
    Tajes, Juan Fernandez
    Highland, Heather M.
    Dupuis, Josee
    Chines, Peter S.
    Lindgren, Cecilia M.
    Hartl, Christopher
    Jackson, Anne U.
    Chen, Han
    Huyghe, Jeroen R.
    van de Bunt, Martijn
    Pearson, Richard D.
    Kumar, Ashish
    Mueller-Nurasyid, Martina
    Grarup, Niels
    Stringham, Heather M.
    Gamazon, Eric R.
    Lee, Jaehoon
    Chen, Yuhui
    Scott, Robert A.
    Below, Jennifer E.
    Chen, Peng
    Huang, Jinyan
    Go, Min Jin
    Stitzel, Michael L.
    Pasko, Dorota
    Parker, Stephen C. J.
    Varga, Tibor V.
    Green, Todd
    Beer, Nicola L.
    Day-Williams, Aaron G.
    Ferreira, Teresa
    Fingerlin, Tasha
    Horikoshi, Momoko
    Hu, Cheng
    Huh, Iksoo
    Ikram, Mohammad Kamran
    Kim, Bong-Jo
    Kim, Yongkang
    Kim, Young Jin
    Kwon, Min-Seok
    Lee, Juyoung
    Lee, Selyeong
    Lin, Keng-Han
    Maxwell, Taylor J.
    Nagai, Yoshihiko
    Wang, Xu
    Welch, Ryan P.
    Yoon, Joon
    Zhang, Weihua
    Barzilai, Nir
    Voight, Benjamin F.
    Han, Bok-Ghee
    Jenkinson, Christopher P.
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Manning, Alisa
    Ng, Maggie C. Y.
    Palmer, Nicholette D.
    Balkau, Beverley
    Stancakova, Alena
    Abboud, Hanna E.
    Boeing, Heiner
    Giedraitis, Vilmantas
    Prabhakaran, Dorairaj
    Gottesman, Omri
    Scott, James
    Carey, Jason
    Kwan, Phoenix
    Grant, George
    Smith, Joshua D.
    Neale, Benjamin M.
    Purcell, Shaun
    Butterworth, Adam S.
    Howson, Joanna M. M.
    Lee, Heung Man
    Lu, Yingchang
    Kwak, Soo-Heon
    Zhao, Wei
    Danesh, John
    Lam, Vincent K. L.
    Park, Kyong Soo
    Saleheen, Danish
    So, Wing Yee
    Tam, Claudia H. T.
    Afzal, Uzma
    Aguilar, David
    Arya, Rector
    Aung, Tin
    Chan, Edmund
    Navarro, Carmen
    Cheng, Ching-Yu
    Palli, Domenico
    Correa, Adolfo
    Curran, Joanne E.
    Rybin, Denis
    Farook, Vidya S.
    Fowler, Sharon P.
    Freedman, Barry I.
    Griswold, Michael
    Hale, Daniel Esten
    Hicks, Pamela J.
    Khor, Chiea-Chuen
    Kumar, Satish
    Lehne, Benjamin
    Thuillier, Dorothee
    Lim, Wei Yen
    Liu, Jianjun
    van der Schouw, Yvonne T.
    Loh, Marie
    Musani, Solomon K.
    Puppala, Sobha
    Scott, William R.
    Yengo, Loic
    Tan, Sian-Tsung
    Taylor, Herman A., Jr.
    Thameem, Farook
    Wilson, Gregory, Sr.
    Wong, Tien Yin
    Njolstad, Pal Rasmus
    Levy, Jonathan C.
    Mangino, Massimo
    Bonnycastle, Lori L.
    Schwarzmayr, Thomas
    Fadista, Joao
    Surdulescu, Gabriela L.
    Herder, Christian
    Groves, Christopher J.
    Wieland, Thomas
    Bork-Jensen, Jette
    Brandslund, Ivan
    Christensen, Cramer
    Koistinen, Heikki A.
    Doney, Alex S. F.
    Kinnunen, Leena
    Esko, Tonu
    Farmer, Andrew J.
    Hakaste, Liisa
    Hodgkiss, Dylan
    Kravic, Jasmina
    Lyssenko, Valeriya
    Hollensted, Mette
    Jorgensen, Marit E.
    Jorgensen, Torben
    Ladenvall, Claes
    Justesen, Johanne Marie
    Karajamaki, Annemari
    Kriebel, Jennifer
    Rathmann, Wolfgang
    Lannfelt, Lars
    Lauritzen, Torsten
    Narisu, Narisu
    Linneberg, Allan
    Melander, Olle
    Milani, Lili
    Neville, Matt
    Orho-Melander, Marju
    Qi, Lu
    Qi, Qibin
    Roden, Michael
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Swift, Amy
    Rosengren, Anders H.
    Stirrups, Kathleen
    Wood, Andrew R.
    Mihailov, Evelin
    Blancher, Christine
    Carneiro, Mauricio O.
    Maguire, Jared
    Poplin, Ryan
    Shakir, Khalid
    Fennell, Timothy
    DePristo, Mark
    de Angelis, Martin Hrabe
    Deloukas, Panos
    Gjesing, Anette P.
    Jun, Goo
    Nilsson, Peter
    Murphy, Jacquelyn
    Onofrio, Robert
    Thorand, Barbara
    Hansen, Torben
    Meisinger, Christa
    Hu, Frank B.
    Isomaa, Bo
    Karpe, Fredrik
    Liang, Liming
    Peters, Annette
    Huth, Cornelia
    O'Rahilly, Stephen P.
    Palmer, Colin N. A.
    Pedersen, Oluf
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Watanabe, Richard M.
    Syvanen, Ann-Christine
    Bergman, Richard N.
    Bharadwaj, Dwaipayan
    Bottinger, Erwin P.
    Cho, Yoon Shin
    Chandak, Giriraj R.
    Chan, Juliana C. N.
    Chia, Kee Seng
    Daly, Mark J.
    Ebrahim, Shah B.
    Langenberg, Claudia
    Elliott, Paul
    Jablonski, Kathleen A.
    Lehman, Donna M.
    Jia, Weiping
    Ma, Ronald C. W.
    Pollin, Toni I.
    Sandhu, Manjinder
    Tandon, Nikhil
    Froguel, Philippe
    Barroso, Ines
    Teo, Yik Ying
    Zeggini, Eleftheria
    Loos, Ruth J. F.
    Small, Kerrin S.
    Ried, Janina S.
    DeFronzo, Ralph A.
    Grallert, Harald
    Glaser, Benjamin
    Metspalu, Andres
    Wareham, Nicholas J.
    Walker, Mark
    Banks, Eric
    Gieger, Christian
    Ingelsson, Erik
    Im, Hae Kyung
    Illig, Thomas
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Buck, Gemma
    Trakalo, Joseph
    Buck, David
    Prokopenko, Inga
    Magi, Reedik
    Lind, Lars
    Farjoun, Yossi
    Owen, Katharine R.
    Gloyn, Anna L.
    Strauch, Konstantin
    Tuomi, Tiinamaija
    Kooner, Jaspal Singh
    Lee, Jong-Young
    Park, Taesung
    Donnelly, Peter
    Morris, Andrew D.
    Hattersley, Andrew T.
    Bowden, Donald W.
    Collins, Francis S.
    Atzmon, Gil
    Chambers, John C.
    Spector, Timothy D.
    Laakso, Markku
    Strom, Tim M.
    Bell, Graeme I.
    Blangero, John
    Duggirala, Ravindranath
    Tai, E. Shyong
    McVean, Gilean
    Hanis, Craig L.
    Wilson, James G.
    Seielstad, Mark
    Frayling, Timothy M.
    Meigs, James B.
    Cox, Nancy J.
    Sladek, Rob
    Lander, Eric S.
    Gabriel, Stacey
    Burtt, Noel P.
    Mohlke, Karen L.
    Meitinger, Thomas
    Groop, Leif
    Abecasis, Goncalo
    Florez, Jose C.
    Scott, Laura J.
    Morris, Andrew P.
    Kang, Hyun Min
    Boehnke, Michael
    Altshuler, David
    McCarthy, Mark I.
    The genetic architecture of type 2 diabetes2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, no 7614, p. 41-47Article in journal (Refereed)
    Abstract [en]

    The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

  • 82. Garzón, J.
    et al.
    Rodríguez, R.
    Kong, Ziqing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rodríguez-Acebes, S.
    Méndez, J.
    Moreno, S.
    García-Higuera, I.
    Shortage of dNTPs underlies altered replication dynamics and DNA breakage in the absence of the APC/C cofactor Cdh12017In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, no 42, p. 5808-5818Article in journal (Refereed)
    Abstract [en]

    The APC/C-Cdh1 ubiquitin-ligase complex targets cell cycle regulators for proteosomal degradation and helps prevent tumor development and accumulation of chromosomal aberrations. Replication stress has been proposed to be the main driver of genomic instability in the absence of Cdh1, but the real contribution of APC/C-Cdh1 to efficient replication, especially in normal cells, remains unclear. Here we show that, in primary MEFs, acute depletion or permanent ablation of Cdh1 slowed down replication fork movement and increased origin activity. Partial inhibition of origin firing does not accelerate replication forks, suggesting that fork progression is intrinsically limited in the absence of Cdh1. Moreover, exogenous supply of nucleotide precursors, or ectopic overexpression of RRM2, the regulatory subunit of Ribonucleotide Reductase, restore replication efficiency, indicating that dNTP availability could be impaired upon Cdh1 loss. Indeed, we found reduced dNTP levels in Cdh1-deficient MEFs. Importantly, DNA breakage is also significantly alleviated by increasing intracellular dNTP pools, strongly suggesting that genomic instability is the result of aberrant replication. These observations highlight the relevance of APC/C-Cdh1 activity during G1 to ensure an adequate supply of dNTPs to the replisome, prevent replication stress and the resulting chromosomal breaks and, ultimately, suppress tumorigenesis.

  • 83. Gaulton, Kyle J.
    et al.
    Ferreira, Teresa
    Lee, Yeji
    Raimondo, Anne
    Maegi, Reedik
    Reschen, Michael E.
    Mahajan, Anubha
    Locke, Adam
    Rayner, N. William
    Robertson, Neil
    Scott, Robert A.
    Prokopenko, Inga
    Scott, Laura J.
    Green, Todd
    Sparso, Thomas
    Thuillier, Dorothee
    Yengo, Loic
    Grallert, Harald
    Wahl, Simone
    Franberg, Mattias
    Strawbridge, Rona J.
    Kestler, Hans
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Karssen, Lennart C.
    van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Li, Man
    Chen, Han
    Fuchsberger, Christian
    Kwan, Phoenix
    Ma, Clement
    Linderman, Michael
    Lu, Yingchang
    Thomsen, Soren K.
    Rundle, Jana K.
    Beer, Nicola L.
    van de Bunt, Martijn
    Chalisey, Anil
    Kang, Hyun Min
    Voight, Benjamin F.
    Abecasis, Goncalo R.
    Almgren, Peter
    Baldassarre, Damiano
    Balkau, Beverley
    Benediktsson, Rafn
    Blueher, Matthias
    Boeing, Heiner
    Bonnycastle, Lori L.
    Bottinger, Erwin P.
    Burtt, Noel P.
    Carey, Jason
    Charpentier, Guillaume
    Chines, Peter S.
    Cornelis, Marilyn C.
    Couper, David J.
    Crenshaw, Andrew T.
    van Dam, Rob M.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Eriksson, Johan G.
    Esko, Tonu
    Eury, Elodie
    Fadista, Joao
    Flannick, Jason
    Fontanillas, Pierre
    Fox, Caroline
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA; Lund University Diabetes Centre, Department of Clinical Science Malmö, Scania University Hospital, Lund University, Malmö, Sweden; Department of Clinical Sciences, Lund University, Malmö, Sweden..
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Gottesman, Omri
    Grant, George B.
    Grarup, Niels
    Groves, Christopher J.
    Hassinen, Maija
    Have, Christian T.
    Herder, Christian
    Holmen, Oddgeir L.
    Hreidarsson, Astradur B.
    Humphries, Steve E.
    Hunter, David J.
    Jackson, Anne U.
    Jonsson, Anna
    Jorgensen, Marit E.
    Jorgensen, Torben
    Kao, Wen-Hong L.
    Kerrison, Nicola D.
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Kovacs, Peter
    Kraft, Peter
    Kravic, Jasmina
    Langford, Cordelia
    Leander, Karin
    Liang, Liming
    Lichtner, Peter
    Lindgren, Cecilia M.
    Lindholm, Eero
    Linneberg, Allan
    Liu, Ching-Ti
    Lobbens, Stephane
    Luan, Jian'an
    Lyssenko, Valeriya
    Mannisto, Satu
    McLeod, Olga
    Meyer, Julia
    Mihailov, Evelin
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Mueller-Nurasyid, Martina
    Navarro, Carmen
    Noethen, Markus M.
    Oskolkov, Nikolay N.
    Owen, Katharine R.
    Palli, Domenico
    Pechlivanis, Sonali
    Peltonen, Leena
    Perry, John R. B.
    Platou, Carl G. P.
    Roden, Michael
    Ruderfer, Douglas
    Rybin, Denis
    van der Schouw, Yvonne T.
    Sennblad, Bengt
    Sigurdsson, Gunnar
    Stancakova, Alena
    Steinbach, Gerald
    Storm, Petter
    Strauch, Konstantin
    Stringham, Heather M.
    Sun, Qi
    Thorand, Barbara
    Tikkanen, Emmi
    Tonjes, Anke
    Trakalo, Joseph
    Tremoli, Elena
    Tuomi, Tiinamaija
    Wennauer, Roman
    Wiltshire, Steven
    Wood, Andrew R.
    Zeggini, Eleftheria
    Dunham, Ian
    Birney, Ewan
    Pasquali, Lorenzo
    Ferrer, Jorge
    Loos, Ruth J. F.
    Dupuis, Josee
    Florez, Jose C.
    Boerwinkle, Eric
    Pankow, James S.
    van Duijn, Cornelia
    Sijbrands, Eric
    Meigs, James B.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Lakka, Timo A.
    Rauramaa, Rainer
    Stumvoll, Michael
    Pedersen, Nancy L.
    Lind, Lars
    Keinanen-Kiukaanniemi, Sirkka M.
    Korpi-Hyovalti, Eeva
    Saaristo, Timo E.
    Saltevo, Juha
    Kuusisto, Johanna
    Laakso, Markku
    Metspalu, Andres
    Erbel, Raimund
    Joecke, Karl-Heinz
    Moebus, Susanne
    Ripatti, Samuli
    Salomaa, Veikko
    Ingelsson, Erik
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Koistinen, Heikki
    Tuomilehto, Jaakko
    Hveem, Kristian
    Njolstad, Inger
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    de Faire, Ulf
    Hamsten, Anders
    Illig, Thomas
    Peters, Annette
    Cauchi, Stephane
    Sladek, Rob
    Froguel, Philippe
    Hansen, Torben
    Pedersen, Oluf
    Morris, Andrew D.
    Palmer, Collin N. A.
    Kathiresan, Sekar
    Melander, Olle
    Nilsson, Peter M.
    Groop, Leif C.
    Barroso, Ines
    Langenberg, Claudia
    Wareham, Nicholas J.
    O'Callaghan, Christopher A.
    Gloyn, Anna L.
    Altshuler, David
    Boehnke, Michael
    Teslovich, Tanya M.
    McCarthy, Mark I.
    Morris, Andrew P.
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, p. 1415-1425Article in journal (Refereed)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

  • 84. Georgiadis, Panagiotis
    et al.
    Liampa, Irene
    Hebels, Dennie G
    Krauskopf, Julian
    Chatziioannou, Aristotelis
    Valavanis, Ioannis
    de Kok, Theo M C M
    Kleinjans, Jos C S
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palli, Domenico
    Vermeulen, R C H
    Vlaanderen, J
    Chadeau-Hyam, Marc
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 728Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.

    RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.

    CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.

  • 85. Giddaluru, Sudheer
    et al.
    Espeseth, Thomas
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet and Stockholm University, 11330 Stockholm, Sweden.
    Westlye, Lars T
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Christoforou, Andrea
    Cichon, Sven
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Steen, Vidar M
    Reinvang, Ivar
    Nilsson, Lars Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). ARC, Karolinska Institutet, Stockholm, Sweden.
    Le Hellard, Stéphanie
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Genetics of structural connectivity and information processing in the brain2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 9, p. 4643-4661Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.

  • 86.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Gärskog, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 32579Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.

  • 87.
    Hagglund, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jones, Iwan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development2017In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 10, no 3, p. 245-257Article in journal (Refereed)
    Abstract [en]

    Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

  • 88. Hahn-Stromberg, Victoria
    et al.
    Askari, Shlear
    Befekadu, Rahel
    Matthiessen, Peter
    Karlsson, Sune
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 7, p. 636-642Article in journal (Refereed)
    Abstract [en]

    Tight junction is composed of transmembrane proteins important for maintaining cell polarity and regulating ion flow. Among these proteins are the tissue-specific claudins, proteins that have recently been suggested as tumor markers for several different types of cancer. An altered claudin expression has been observed in colon, prostatic, ovarian, and breast carcinoma. The aim of this study was to analyze the allele frequencies of three common single nucleotide polymorphisms (SNPs) in the genes for claudin 1 and claudin 7 in colon cancer (CC) patients and in a control population of healthy blood donors. Pyrosequencing was used to genotype the CLDN1 SNP rs9869263 (c.369C>T), and the CLDN7 SNPs rs4562 (c.590C>T) and rs374400 (c.606T>G) in DNA from 102 formalin fixed paraffin embedded (FFPE) colon cancer tissue, and 111 blood leukocyte DNA from blood/plasma donors. These results were correlated with clinical parameters such as TNM stage, tumor localization, tumor differentiation, complexity index, sex, and age. We found that there was a significant association between the CLDN1 genotype CC in tumor samples and a higher risk of colon cancer development (OR 3.0, p < 0.001). We also found that the CLDN7 rs4562 (c.590C>T) genotype CT had a higher risk of lymph node involvement (p = 0.031) and a lower degree of tumor differentiation (p = 0.028). In the control population, the allele frequencies were very similar to those in the HapMap cohort for CLDN7. The CLDN1 rs9869263 genotype (c.369C>T) was related to increased risk of colon cancer, and the CLDN7 rs4562 genotype (c.590C>T) was related to tumor differentiation and lymph node involvement in colon carcinoma. Further studies are warranted to ascertain their potential uses as biomarkers predicting tumor development, proliferation, and outcome in this disease.

  • 89.
    Hall, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Lindberg, Mikael J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sauer, Uwe H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Structural basis for glutathione-mediated activation of the virulence regulatory protein PrfA in Listeria2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 51, p. 14733-14738Article in journal (Refereed)
    Abstract [en]

    Infection by the human bacterial pathogen Listeria monocytogenes is mainly controlled by the positive regulatory factor A (PrfA), a member of the Crp/Fnr family of transcriptional activators. Published data suggest that PrfA requires the binding of a cofactor for full activity, and it was recently proposed that glutathione (GSH) could fulfill this function. Here we report the crystal structures of PrfA in complex with GSH and in complex with GSH and its cognate DNA, the hly operator PrfA box motif. These structures reveal the structural basis for a GSH-mediated allosteric mode of activation of PrfA in the cytosol of the host cell. The crystal structure of PrfAWT in complex only with DNA confirms that PrfAWT can adopt a DNA binding-compatible structure without binding the GSH activator molecule. By binding to PrfA in the cytosol of the host cell, GSH induces the correct fold of the HTH motifs, thus priming the PrfA protein for DNA interaction.

  • 90. Han, Buhm
    et al.
    Diogo, Dorothee
    Eyre, Steve
    Kallberg, Henrik
    Zhernakova, Alexandra
    Bowes, John
    Padyukov, Leonid
    Okada, Yukinori
    Gonzalez-Gay, Miguel A.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Martin, Javier
    Huizinga, Tom W. J.
    Plenge, Robert M.
    Worthington, Jane
    Gregersen, Peter K.
    Klareskog, Lars
    de Bakker, Paul I. W.
    Raychaudhuri, Soumya
    Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity2014In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 94, no 4, p. 522-532Article in journal (Refereed)
    Abstract [en]

    Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.

  • 91. Han, Buhm
    et al.
    Pouget, Jennie G.
    Slowikowski, Kamil
    Stahl, Eli
    Lee, Cue Hyunkyu
    Diogo, Dorothee
    Hu, Xinli
    Park, Yu Rang
    Kim, Eunji
    Gregersen, Peter K.
    Dahlqvist, Solbritt Rantapää
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Worthington, Jane
    Martin, Javier
    Eyre, Steve
    Klareskog, Lars
    Huizinga, Tom
    Chen, Wei-Min
    Onengut-Gumuscu, Suna
    Rich, Stephen S.
    Wray, Naomi R.
    Raychaudhuri, Soumya
    A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 7, p. 803-+Article in journal (Refereed)
    Abstract [en]

    There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data. We observed a shared genetic basis for 11 autoimmune diseases and type 1 diabetes (T1D; P < 1 x 10(-4)) and for 11 autoimmune diseases and rheumatoid arthritis (RA; P < 1 x 10(-3)). This sharing was not explained by subgroup heterogeneity (corrected P-BUHMBOX > 0.2; 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (P < 1 x 10(-9)) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (P-BUHMBOX = 0.008; 2,406 seronegative RA cases). We also observed a shared genetic basis for major depressive disorder (MDD) and schizophrenia (P < 1 x 10(-4)) that was not explained by subgroup heterogeneity (P-BUHMBOX = 0.28; 9,238 MDD cases).

  • 92. Harrison, C. J.
    et al.
    Moorman, A. V.
    Schwab, C.
    Carroll, A. J.
    Raetz, E. A.
    Devidas, M.
    Strehl, S.
    Nebral, K.
    Harbott, J.
    Teigler-Schlegel, A.
    Zimmerman, M.
    Dastuge, N.
    Baruchel, A.
    Soulier, J.
    Auclerc, M-F
    Attarbaschi, A.
    Mann, G.
    Stark, B.
    Cazzaniga, G.
    Chilton, L.
    Vandenberghe, P.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Haltrich, I.
    Raimondi, S. C.
    Parihar, M.
    Bourquin, J-P
    Tchinda, J.
    Haferlach, C.
    Vora, A.
    Hunger, S. P.
    Heerema, N. A.
    Haas, O. A.
    An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome2014In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 5, p. 1015-1021Article in journal (Refereed)
    Abstract [en]

    Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.

  • 93.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Westermark, Per
    Stafberg, Christina
    Nahi, Hareth
    Tachlinski, Sascha
    Guggi, Michael
    Flogegard, Max
    Hamid, Mehmet
    Andersson Escher, Stefan
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family2015In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 58, no 4, p. 211-215Article in journal (Refereed)
    Abstract [en]

    In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (similar to 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. In conclusion: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

  • 94. Hens, Kristien
    et al.
    Cutas, DanielaUmeå University, Faculty of Arts, Department of historical, philosophical and religious studies. Department of Philosopy, Linguistics and Theory of Science University of Gothenburg Gothenburg, Sweden.Horstkötter, Dorothee
    Parental responsibility in the context of neuroscience and genetics2017Collection (editor) (Refereed)
    Abstract [en]

    Should parents aim to make their children as normal as possible to increase their chances to "fit in"? Are neurological and mental health conditions a part of children's identity and if so, should parents aim to remove or treat these? Should they aim to instill self-control in their children? Should prospective parents take steps to insure that, of all the children they could have, they choose the ones with the best likely start in life?

    This volume explores all of these questions and more. Against the background of recent findings and expected advances in neuroscience and genetics, the extent and limits of parental responsibility are increasingly unclear. Awareness of the effects of parental choices on children's wellbeing, as well as evolving norms about the moral status of children, have further increased expectations from (prospective) parents to take up and act on their changing responsibilities. The contributors discuss conceptual issues such as the meaning and sources of moral responsibility, normality, treatment, and identity. They also explore more practical issues such as how responsibility for children is practiced in Yoruba culture in Nigeria or how parents and health professionals in Belgium perceive the dilemmas generated by prenatal diagnosis.

  • 95. Hibar, Derrek P.
    et al.
    Adams, Hieab H. H.
    Jahanshad, Neda
    Chauhan, Ganesh
    Stein, Jason L.
    Hofer, Edith
    Renteria, Miguel E.
    Bis, Joshua C.
    Arias-Vasquez, Alejandro
    Ikram, M. Kamran
    Desrivieres, Sylvane
    Vernooij, Meike W.
    Abramovic, Lucija
    Alhusaini, Saud
    Amin, Najaf
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Arfanakis, Konstantinos
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Athanasiu, Lavinia
    Axelsson, Tomas
    Beecham, Ashley H.
    Beiser, Alexa
    Bernard, Manon
    Blanton, Susan H.
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brickman, Adam M.
    Carmichael, Owen
    Chakravarty, M. Mallar
    Chen, Qiang
    Ching, Christopher R. K.
    Chouraki, Vincent
    Cuellar-Partida, Gabriel
    Crivello, Fabrice
    Den Braber, Anouk
    Doan, Nhat Trung
    Ehrlich, Stefan
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Gottesman, Rebecca F.
    Grimm, Oliver
    Griswold, Michael E.
    Guadalupe, Tulio
    Gutman, Boris A.
    Hass, Johanna
    Haukvik, Unn K.
    Hoehn, David
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Jorgensen, Kjetil N.
    Karbalai, Nazanin
    Kasperaviciute, Dalia
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Liewald, David C. M.
    Lopez, Lorna M.
    Luciano, Michelle
    Macare, Christine
    Marquand, Andre F.
    Matarin, Mar
    Mather, Karen A.
    Mattheisen, Manuel
    McKay, David R.
    Milaneschi, Yuri
    Maniega, Susana Munoz
    Nho, Kwangsik
    Nugent, Allison C.
    Nyquist, Paul
    Loohuis, Loes M. Olde
    Oosterlaan, Jaap
    Papmeyer, Martina
    Pirpamer, Lukas
    Puetz, Benno
    Ramasamy, Adaikalavan
    Richards, Jennifer S.
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rommelse, Nanda
    Ropele, Stefan
    Rose, Emma J.
    Royle, Natalie A.
    Rundek, Tatjana
    Saemann, Philipp G.
    Saremi, Arvin
    Satizabal, Claudia L.
    Schmaal, Lianne
    Schork, Andrew J.
    Shen, Li
    Shin, Jean
    Shumskaya, Elena
    Smith, Albert V.
    Sprooten, Emma
    Strike, Lachlan T.
    Teumer, Alexander
    Tordesillas-Gutierrez, Diana
    Toro, Roberto
    Trabzuni, Daniah
    Trompet, Stella
    Vaidya, Dhananjay
    Van der Grond, Jeroen
    Van der Lee, Sven J.
    Van der Meer, Dennis
    Van Donkelaar, Marjolein M. J.
    Van Eijk, Kristel R.
    Van Erp, Theo G. M.
    Van Rooij, Daan
    Walton, Esther
    Westlye, Lars T.
    Whelan, Christopher D.
    Windham, Beverly G.
    Winkler, Anderson M.
    Wittfeld, Katharina
    Woldehawariat, Girma
    Wolf, Christiane
    Wolfers, Thomas
    Yanek, Lisa R.
    Yang, Jingyun
    Zijdenbos, Alex
    Zwiers, Marcel P.
    Agartz, Ingrid
    Almasy, Laura
    Ames, David
    Amouyel, Philippe
    Andreassen, Ole A.
    Arepalli, Sampath
    Assareh, Amelia A.
    Barral, Sandra
    Bastin, Mark E.
    Becker, Diane M.
    Becker, James T.
    Bennett, David A.
    Blangero, John
    van Bokhoven, Hans
    Boomsma, Dorret I.
    Brodaty, Henry
    Brouwer, Rachel M.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Bulayeva, Kazima B.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cannon, Dara M.
    Cavalleri, Gianpiero L.
    Cheng, Ching-Yu
    Cichon, Sven
    Cookson, Mark R.
    Corvin, Aiden
    Crespo-Facorro, Benedicto
    Curran, Joanne E.
    Czisch, Michael
    Dale, Anders M.
    Davies, Gareth E.
    De Craen, Anton J. M.
    De Geus, Eco J. C.
    De Jager, Philip L.
    De Zubicaray, Greig I.
    Deary, Ian J.
    Debette, Stephanie
    DeCarli, Charles
    Delanty, Norman
    Depondt, Chantal
    DeStefano, Anita
    Dillman, Allissa
    Djurovic, Srdjan
    Donohoe, Gary
    Drevets, Wayne C.
    Duggirala, Ravi
    Dyer, Thomas D.
    Enzinger, Christian
    Erk, Susanne
    Espeseth, Thomas
    Fedko, Iryna O.
    Fernandez, Guillen
    Ferrucci, Luigi
    Fisher, Simon E.
    Fleischman, Debra A.
    Ford, Ian
    Fornage, Myriam
    Foroud, Tatiana M.
    Fox, Peter T.
    Francks, Clyde
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Glahn, David C.
    Gollub, Randy L.
    Goring, Harald H. H.
    Green, Robert C.
    Gruber, Oliver
    Gudnason, Vilmundur
    Guelfi, Sebastian
    Haberg, Asta K.
    Hansell, Narelle K.
    Hardy, John
    Hartman, Catharina A.
    Hashimoto, Ryota
    Hegenscheid, Katrin
    Heinz, Andreas
    Le Hellard, Stephanie
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Ho, Beng-Choon
    Hoekstra, Pieter J.
    Hoffmann, Wolfgang
    Hofman, Albert
    Holsboer, Florian
    Homuth, Georg
    Hosten, Norbert
    Hottenga, Jouke-Jan
    Huentelman, Matthew
    Pol, Hilleke E. Hulshoff
    Ikeda, Masashi
    Jack, Clifford R., Jr.
    Jenkinson, Mark
    Johnson, Robert
    Joensson, Erik G.
    Jukema, J. Wouter
    Kahn, Rene S.
    Kanai, Ryota
    Kloszewska, Iwona
    Knopman, David S.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Lemaitre, Herve
    Liu, Xinmin
    Longo, Dan L.
    Lopez, Oscar L.
    Lovestone, Simon
    Martinez, Oliver
    Martinot, Jean-Luc
    Mattay, Venkata S.
    McDonald, Colm
    McIntosh, Andrew M.
    McMahon, Francis J.
    McMahon, Katie L.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Mohnke, Sebastian
    Montgomery, Grant W.
    Morris, Derek W.
    Mosley, Thomas H.
    Muhleisen, Thomas W.
    Mueller-Myhsok, Bertram
    Nalls, Michael A.
    Nauck, Matthias
    Nichols, Thomas E.
    Niessen, Wiro J.
    Nothen, Markus M.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ohi, Kazutaka
    Olvera, Rene L.
    Ophoff, Roel A.
    Pandolfo, Massimo
    Paus, Tomas
    Pausova, Zdenka
    Penninx, Brenda W. J. H.
    Pike, G. Bruce
    Potkin, Steven G.
    Psaty, Bruce M.
    Reppermund, Simone
    Rietschel, Marcella
    Roffman, Joshua L.
    Romanczuk-Seiferth, Nina
    Rotter, Jerome I.
    Ryten, Mina
    Sacco, Ralph L.
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter R.
    Sigursson, Sigurdur
    Simmons, Andrew
    Singleton, Andrew
    Sisodiya, Sanjay M.
    Smith, Colin
    Smoller, Jordan W.
    Soininen, Hilkka
    Steen, Vidar M.
    Stott, David J.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Tsolaki, Magda
    Tzourio, Christophe
    Uitterlinden, Andre G.
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    van der Lugt, Aad
    van der Wee, Nic J. A.
    Van Haren, Neeltje E. M.
    van't Ent, Dennis
    Van Tol, Marie-Jose
    Vardarajan, Badri N.
    Vellas, Bruno
    Veltman, Dick J.
    Voelzke, Henry
    Walter, Henrik
    Wardlaw, Joanna M.
    Wassink, Thomas H.
    Weale, Michael E.
    Weinberger, Daniel R.
    Weiner, Michael W.
    Wen, Wei
    Westman, Eric
    White, Tonya
    Wong, Tien Y.
    Wright, Clinton B.
    Zielke, Ronald H.
    Zonderman, Alan B.
    Martin, Nicholas G.
    Van Duijn, Cornelia M.
    Wright, Margaret J.
    Longstreth, W. T.
    Schumann, Gunter
    Grabe, Hans J.
    Franke, Barbara
    Launer, Lenore J.
    Medland, Sarah E.
    Seshadri, Sudha
    Thompson, Paul M.
    Ikram, M. Arfan
    Novel genetic loci associated with hippocampal volume2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 13624Article in journal (Refereed)
    Abstract [en]

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  • 96. Higelin, Julia
    et al.
    Catanese, Alberto
    Semelink-Sedlacek, Lena Luisa
    Oeztuerk, Sertap
    Lutz, Anne-Kathrin
    Bausinger, Julia
    Barbi, Gotthold
    Speit, Güenter
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ludolph, Albert C.
    Demestre, Maria
    Boeckers, Tobias M.
    NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons2018In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 30, p. 150-162Article in journal (Refereed)
    Abstract [en]

    Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS.

  • 97.
    Holmberg, Monica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Jenni
    Forsgren, Lars
    Heijbel, Jan
    Sandgren, Ola
    Holmgren, Gösta
    Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.11995In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 8, p. 1441-1445Article in journal (Refereed)
    Abstract [en]

    We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation, Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II, Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically, During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11), We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers, Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.

  • 98. Hooper, Sean D.
    et al.
    Johansson, Anna C. V.
    Tellgren-Roth, Christian
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Dahl, Niklas
    Cavelier, Lucia
    Feuk, Lars
    Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 123-Article in journal (Refereed)
    Abstract [en]

    Background: Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood. Methods: Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband. Results: Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay. The proband's mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome. Conclusions: We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.

  • 99. Hu, F Z
    et al.
    Nyström, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Department of Plastic Surgery and Department of Orthopedic Surgery, University of Nebraska, Omaha, NE, USA.
    Ahmed, A
    Palmquist, M
    Dopico, R
    Mossberg, I
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Gladitz, J
    Rayner, M
    Post, J C
    Ehrlich, G D
    Preston, R A
    Mapping of an autosomal dominant gene for Dupuytren's contracture to chromosome 16q in a Swedish family2005In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 68, no 5, p. 424-429Article in journal (Refereed)
    Abstract [en]

    Dupuytren's contracture (DC) (OMIM 126900) is the most common connective tissue disease of mankind and has both heritable and sporadic forms. The inherited form is most frequently observed among the xanthochroi peoples of Northern Europe where its most common manifestations are thickening of the palmar fascia and contracture of the fingers. We ascertained a five-generation Swedish family in which DC is inherited in an autosomal dominant manner with high, but incomplete, penetrance by the end of the fifth decade. Blood was collected from all affected and informative unaffected family members for the performance of a genome-wide scan at a resolution of approximately 8 cM for all autosomes. Linkage was established to a single 6 cM region between markers D16S419 and D16S3032 on chromosome 16. A maximal two-point logarithm of odds (LOD) score of 3.18 was achieved at microsatellite marker D16S415 with four other markers in the region producing LODs of > 1.5.

  • 100. Huckins, Laura M.
    et al.
    Dobbyn, Amanda
    Ruderfer, Douglas M.
    Hoffman, Gabriel
    Wang, Weiqing
    Pardinas, Antonio F.
    Rajagopal, Veera M.
    Als, Thomas D.
    Nguyen, Hoang T.
    Girdhar, Kiran
    Boocock, James
    Roussos, Panos
    Fromer, Menachem
    Kramer, Robin
    Domenici, Enrico
    Gamazon, Eric R.
    Purcell, Shaun
    Demontis, Ditte
    Borglum, Anders D.
    Walters, James T. R.
    O'Donovan, Michael C.
    Sullivan, Patrick
    Owen, Michael J.
    Devlin, Bernie
    Sieberts, Solveig K.
    Cox, Nancy J.
    Im, Hae Kyung
    Sklar, Pamela
    Stahl, Eli A.
    Johnson, Jessica S.
    Shah, Hardik R.
    Klein, Lambertus L.
    Dang, Kristen K.
    Logsdon, Benjamin A.
    Mahajan, Milind C.
    Mangravite, Lara M.
    Toyoshiba, Hiroyoshi
    Gur, Raquel E.
    Hahn, Chang-Gyu
    Schadt, Eric
    Lewis, David A.
    Haroutunian, Vahram
    Peters, Mette A.
    Lipska, Barbara K.
    Buxbaum, Joseph D.
    Hirai, Keisuke
    Perumal, Thanneer M.
    Essioux, Laurent
    Rajagopal, Veera Manikandan
    Mattheisen, Manuel
    Grove, Jakob
    Werge, Thomas
    Mortensen, Preben Bo
    Pedersen, Carsten Bocker
    Agerbo, Esben
    Pedersen, Marianne Giortz
    Mors, Ole
    Nordentoft, Merete
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Baekvad-Hansen, Marie
    Hansen, Christine Soholm
    Ripke, Stephan
    Neale, Benjamin M.
    Corvin, Aiden
    Farh, Kai-How
    Holmans, Peter A.
    Lee, Phil
    Bulik-Sullivan, Brendan
    Collier, David A.
    Huang, Hailiang
    Pers, Tune H.
    Agartz, Ingrid
    Albus, Margot
    Alexander, Madeline
    Amin, Farooq
    Bacanu, Silviu A.
    Begemann, Martin
    Belliveau, Richard A., Jr.
    Bene, Judit
    Bergen, Sarah E.
    Bevilacqua, Elizabeth
    Bigdeli, Tim B.
    Black, Donald W.
    Bruggeman, Richard
    Buccola, Nancy G.
    Buckner, Randy L.
    Byerley, William
    Cahn, Wiepke
    Cai, Guiqing
    Campion, Dominique
    Cantor, Rita M.
    Carr, Vaughan J.
    Carrera, Noa
    Catts, Stanley, V
    Chambert, Kimberly D.
    Chan, Raymond C. K.
    Chen, Ronald Y. L.
    Chen, Eric Y. H.
    Cheng, Wei
    Cheung, Eric F. C.
    Chong, Siow Ann
    Cloninger, C. Robert
    Cohen, David
    Cohen, Nadine
    Cormican, Paul
    Craddock, Nick
    Crowley, James J.
    Curtis, David
    Davidson, Michael
    Davis, Kenneth L.
    Degenhardt, Franziska
    Del Favero, Jurgen
    Dikeos, Dimitris
    Dinan, Timothy
    Djurovic, Srdjan
    Donohoe, Gary
    Drapeau, Elodie
    Duan, Jubao
    Dudbridge, Frank
    Durmishi, Naser
    Eichhammer, Peter
    Eriksson, Johan
    Escott-Price, Valentina
    Fanous, Ayman H.
    Farrell, Martilias S.
    Frank, Josef
    Franke, Lude
    Freedman, Robert
    Freimer, Nelson B.
    Friedl, Marion
    Friedman, Joseph, I
    Genovese, Giulio
    Georgieva, Lyudmila
    Giegling, Ina
    Giusti-Rodriguez, Paola
    Godard, Stephanie
    Goldstein, Jacqueline, I
    Golimbet, Vera
    Gopal, Srihari
    Gratten, Jacob
    de Haan, Lieuwe
    Hammer, Christian
    Hamshere, Marian L.
    Hansen, Mark
    Hansen, Thomas
    Hartmann, Annette M.
    Henskens, Frans A.
    Herms, Stefan
    Hirschhorn, Joel N.
    Hoffmann, Per
    Hofman, Andrea
    Hollegaard, Mads, V
    Ikeda, Masashi
    Joa, Inge
    Julia, Antonio
    Kahn, Rene S.
    Kalaydjieva, Luba
    Karachanak-Yankova, Sena
    Karjalainen, Juha
    Kavanagh, David
    Keller, Matthew C.
    Kennedy, James L.
    Khrunin, Andrey
    Kim, Yunjung
    Klovins, Janis
    Knowles, James A.
    Konte, Bettina
    Kucinskas, Vaidutis
    Kucinskiene, Zita Ausrele
    Kuzelova-Ptackova, Hana
    Kahler, Anna K.
    Laurent, Claudine
    Keong, Jimmy Lee Chee
    Lee, S. Hong
    Legge, Sophie E.
    Lerer, Bernard
    Li, Miaoxin
    Li, Tao
    Liang, Kung-Yee
    Lieberman, Jeffrey
    Limborska, Svetlana
    Loughland, Carmel M.
    Lubinski, Jan
    Lonnqvist, Jouko
    Macek, Milan, Jr.
    Magnusson, Patrik K. E.
    Maher, Brion S.
    Maier, Wolfgang
    Mallet, Jacques
    Marsal, Sara
    Mattingsdal, Morten
    McCarley, Robert W.
    McDonald, Colm
    McIntosh, Andrew M.
    Meier, Sandra
    Meijer, Carin J.
    Melegh, Bela
    Melle, Ingrid
    Mesholam-Gately, Raquelle, I
    Metspalu, Andres
    Michie, Patricia T.
    Milani, Lili
    Milanova, Vihra
    Mokrab, Younes
    Morris, Derek W.
    Murphy, Kieran C.
    Murray, Robin M.
    Myin-Germeys, Inez
    Muller-Myhsok, Bertram
    Nelis, Mari
    Nenadic, Igor
    Nertney, Deborah A.
    Nestadt, Gerald
    Nicodemus, Kristin K.
    Nikitina-Zake, Liene
    Nisenbaum, Laura
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    O'Callaghan, Eadbhard
    O'Dushlaine, Colm
    O'Neill, F. Anthony
    Oh, Sang-Yun
    Olincy, Ann
    Olsen, Line
    Van Os, Jim
    Pantelis, Christos
    Papadimitriou, George N.
    Papiol, Sergi
    Parkhomenko, Elena
    Pato, Michele T.
    Paunio, Tiina
    Pejovic-Milovancevic, Milica
    Perkins, Diana O.
    Pietilainen, Olli
    Pimm, Jonathan
    Pocklington, Andrew J.
    Powell, John
    Price, Alkes
    Pulver, Ann E.
    Purcell, Shaun M.
    Quested, Digby
    Rasmussen, Henrik B.
    Reichenberg, Abraham
    Reimers, Mark A.
    Richards, Alexander L.
    Roffman, Joshua L.
    Salomaa, Veikko
    Sanders, Alan R.
    Schall, Ulrich
    Schubert, Christian R.
    Schulze, Thomas G.
    Schwab, Sibylle G.
    Scolnick, Edward M.
    Scott, Rodney J.
    Seidman, Larry J.
    Shi, Jianxin
    Sigurdsson, Engilbert
    Silagadze, Teimuraz
    Silverman, Jeremy M.
    Sim, Kang
    Slominsky, Petr
    Smoller, Jordan W.
    So, Hon-Cheong
    Spencer, Chris C. A.
    Stefansson, Hreinn
    Steinberg, Stacy
    Stogmann, Elisabeth
    Straub, Richard E.
    Strengman, Eric
    Strohmaier, Jana
    Stroup, T. Scott
    Subramaniam, Mythily
    Suvisaari, Jaana
    Svrakic, Dragan M.
    Szatkiewicz, Jin P.
    Soderman, Erik
    Thirumalai, Srinivas
    Toncheva, Draga
    Tosato, Sarah
    Veijola, Juha
    Waddington, John
    Walsh, Dermot
    Wang, Dai
    Wang, Qiang
    Webb, Bradley T.
    Weiser, Mark
    Wildenauer, Dieter B.
    Williams, Nigel M.
    Williams, Stephanie
    Witt, Stephanie H.
    Wolen, Aaron R.
    Wong, Emily H. M.
    Wormley, Brandon K.
    Xi, Hualin Simon
    Zai, Clement C.
    Zheng, Xuebin
    Zimprich, Fritz
    Wray, Naomi R.
    Stefansson, Kari
    Visscher, Peter M.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Andreassen, Ole A.
    Blackwood, Douglas H. R.
    Bramon, Elvira
    Cichon, Sven
    Darvasi, Ariel
    Ehrenreich, Hannelore
    Esko, Tonu
    Gejman, Pablo, V
    Gill, Michael
    Gurling, Hugh
    Hultman, Christina M.
    Iwata, Nakao
    Jablensky, Assen, V
    Jonsson, Erik G.
    Kendler, Kenneth S.
    Kirov, George
    Knight, Jo
    Lencz, Todd
    Levinson, Douglas F.
    Li, Qingqin S.
    Liu, Jianjun
    Malhotra, Anil K.
    McCarroll, Steven A.
    McQuillin, Andrew
    Moran, Jennifer L.
    Mortensen, Preben B.
    Mowry, Bryan J.
    Nothen, Markus M.
    Ophoff, Roel A.
    Palotie, Aarno
    Pato, Carlos N.
    Petryshen, Tracey L.
    Posthuma, Danielle
    Rietschel, Marcella
    Riley, Brien P.
    Rujescu, Dan
    Sham, Pak C.
    St Clair, David
    Weinberger, Daniel R.
    Wendland, Jens R.
    Daly, Mark J.
    Sullivan, Patrick F.
    Gene expression imputation across multiple brain regions provides insights into schizophrenia risk2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 4, p. 659-+Article in journal (Refereed)
    Abstract [en]

    Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

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