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  • 251.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    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, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish landscape of hereditary ATTR amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 93-94Article in journal (Refereed)
    Abstract [en]

    Northern Sweden is a well-known clustering area for hereditary transthyretin (TTR) amyloid (ATTR) amyloidosis caused by the Val30Met mutation. However, several additional mutations have been found in the Swedish population, of which many, such as the Ala45Ser, Gly57Arg and His88Arg mutations, have not been reported outside of Sweden to the best of our knowledge. We aim to give an overview of the various mutations found in the Swedish population.

  • 252. Sung, Yun J.
    et al.
    Winkler, Thomas W.
    de las Fuentes, Lisa
    Bentley, Amy R.
    Brown, Michael R.
    Kraja, Aldi T.
    Schwander, Karen
    Ntalla, Ioanna
    Guo, Xiuqing
    Franceschini, Nora
    Lu, Yingchang
    Cheng, Ching-Yu
    Sim, Xueling
    Vojinovic, Dina
    Marten, Jonathan
    Musani, Solomon K.
    Li, Changwei
    Feitosa, Mary F.
    Kilpelainen, Tuomas O.
    Richard, Melissa A.
    Noordam, Raymond
    Aslibekyan, Stella
    Aschard, Hugues
    Bartz, Traci M.
    Dorajoo, Rajkumar
    Liu, Yongmei
    Manning, Alisa K.
    Rankinen, Tuomo
    Smith, Albert Vernon
    Tajuddin, Salman M.
    Tayo, Bamidele O.
    Warren, Helen R.
    Zhao, Wei
    Zhou, Yanhua
    Matoba, Nana
    Sofer, Tamar
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Gandin, Ilaria
    Gao, Chuan
    Giulianini, Franco
    Goel, Anuj
    Harris, Sarah E.
    Hartwig, Fernando Pires
    Horimoto, Andrea R. V. R.
    Hsu, Fang-Chi
    Jackson, Anne U.
    Kahonen, Mika
    Kasturiratne, Anuradhani
    Kuhnel, Brigitte
    Leander, Karin
    Lee, Wen-Jane
    Lin, Keng-Hung
    Luan, Jian' an
    McKenzie, Colin A.
    Meian, He
    Nelson, Christopher P.
    Rauramaa, Rainer
    Schupf, Nicole
    Scott, Robert A.
    Sheu, Wayne H. H.
    Stancakova, Alena
    Takeuchi, Fumihiko
    van der Most, Peter J.
    Varga, Tibor V.
    Wang, Heming
    Wang, Yajuan
    Ware, Erin B.
    Weiss, Stefan
    Wen, Wanqing
    Yanek, Lisa R.
    Zhang, Weihua
    Zhao, Jing Hua
    Afaq, Saima
    Alfred, Tamuno
    Amin, Najaf
    Arking, Dan
    Aung, Tin
    Barr, R. Graham
    Bielak, Lawrence F.
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Braund, Peter S.
    Brody, Jennifer A.
    Broeckel, Ulrich
    Cabrera, Claudia P.
    Cade, Brian
    Caizheng, Yu
    Campbell, Archie
    Canouil, Mickael
    Chakravarti, Aravinda
    Chauhan, Ganesh
    Christensen, Kaare
    Cocca, Massimiliano
    Collins, Francis S.
    Connell, John M.
    de Mutsert, Renee
    de Silva, H. Janaka
    Debette, Stephanie
    Dorr, Marcus
    Duan, Qing
    Eaton, Charles B.
    Ehret, Georg
    Evangelou, Evangelos
    Faul, Jessica D.
    Fisher, Virginia A.
    Forouhi, Nita G.
    Franco, Oscar H.
    Friedlander, Yechiel
    Gao, He
    Gigante, Bruna
    Graff, Misa
    Gu, C. Charles
    Gu, Dongfeng
    Gupta, Preeti
    Hagenaars, Saskia P.
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hirata, Makoto
    Hofman, Albert
    Howard, Barbara V.
    Hunt, Steven
    Irvin, Marguerite R.
    Jia, Yucheng
    Joehanes, Roby
    Justice, Anne E.
    Katsuya, Tomohiro
    Kaufman, Joel
    Kerrison, Nicola D.
    Khor, Chiea Chuen
    Koh, Woon-Puay
    Koistinen, Heikki A.
    Komulainen, Pirjo
    Kooperberg, Charles
    Krieger, Jose E.
    Kubo, Michiaki
    Kuusisto, Johanna
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Lehne, Benjamin
    Lewis, Cora E.
    Li, Yize
    Lim, Sing Hui
    Lin, Shiow
    Liu, Ching-Ti
    Liu, Jianjun
    Liu, Jingmin
    Liu, Kiang
    Liu, Yeheng
    Loh, Marie
    Lohman, Kurt K.
    Long, Jirong
    Louie, Tin
    Magi, Reedik
    Mahajan, Anubha
    Meitinger, Thomas
    Metspalu, Andres
    Milani, Lili
    Momozawa, Yukihide
    Morris, Andrew P.
    Mosley, Thomas H., Jr.
    Munson, Peter
    Murray, Alison D.
    Nalls, Mike A.
    Nasri, Ubaydah
    Norris, Jill M.
    North, Kari
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R.
    Palmer, Nicholette D.
    Pankow, James S.
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Raitakari, Olli T.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Rice, Treva K.
    Ridker, Paul M.
    Robino, Antonietta
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Sabanayagam, Charumathi
    Salako, Babatunde L.
    Sandow, Kevin
    Schmidt, Carsten O.
    Schreiner, Pamela J.
    Scott, William R.
    Seshadri, Sudha
    Sever, Peter
    Sitlani, Colleen M.
    Smith, Jennifer A.
    Snieder, Harold
    Starr, John M.
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Teo, Yik Ying
    Tham, Yih Chung
    Ultterlinden, Andre G.
    Waldenberger, Melanie
    Wang, Lihua
    Wang, Ya X.
    Bin Wei, Wen
    Williams, Christine
    Wilson, Gregory
    Wojczynski, Mary K.
    Yao, Jie
    Yuan, Jian-Min
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    Chambers, John C.
    Chen, Yii-Der Ida
    de Faire, Ulf
    Deary, Ian J.
    Esko, Tonu
    Farrall, Martin
    Forrester, Terrence
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden; Harvard T.H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA, USA.
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Horta, Bernardo Lessa
    Hung, Yi-Jen
    Jonas, Jost B.
    Kato, Norihiro
    Kooner, Jaspal S.
    Laakso, Markku
    Lehtimaki, Terho
    Liang, Kae-Woei
    Magnusson, Patrik K. E.
    Newman, Anne B.
    Oldehinkel, Albertine J.
    Pereira, Alexandre C.
    Redline, Susan
    Rettig, 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
    Kamatani, Yoichiro
    Laurie, Cathy C.
    Bouchard, Claude
    Cooper, Richard S.
    Evans, Michele K.
    Gudnason, Vilmundur
    Kardia, Sharon L. R.
    Kritchevsky, Stephen B.
    Levy, Daniel
    O'Connell, Jeff R.
    Psaty, Bruce M.
    van Dam, Rob M.
    Sims, Mario
    Arnett, Donna K.
    Mook-Kanamori, Dennis O.
    Kelly, Tanika N.
    Fox, Ervin R.
    Hayward, Caroline
    Fornage, Myriam
    Rotimi, Charles N.
    Province, Michael A.
    van Duijn, Cornelia M.
    Tai, E. Shyong
    Wong, Tien Yin
    Loos, Ruth J. F.
    Reiner, Alex P.
    Rotter, Jerome I.
    Zhu, Xiaofeng
    Bierut, Laura J.
    Gauderman, W. James
    Caulfield, Mark J.
    Elliott, Paul
    Rice, Kenneth
    Munroe, Patricia B.
    Morrison, Alanna C.
    Cupples, L. Adrienne
    Rao, Dabeeru C.
    Chasman, Daniel I.
    A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 3, p. 375-400Article in journal (Refereed)
    Abstract [en]

    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).

  • 253. Surendran, Praveen
    et al.
    Drenos, Fotios
    Young, Robin
    Warren, Helen
    Cook, James P.
    Manning, Alisa K.
    Grarup, Niels
    Sim, Xueling
    Barnes, Daniel R.
    Witkowska, Kate
    Staley, James R.
    Tragante, Vinicius
    Tukiainen, Taru
    Yaghootkar, Hanieh
    Masca, Nicholas
    Freitag, Daniel F.
    Ferreira, Teresa
    Giannakopoulou, Olga
    Tinker, Andrew
    Harakalova, Magdalena
    Mihailov, Evelin
    Liu, Chunyu
    Kraja, Aldi T.
    Nielsen, Sune Fallgaard
    Rasheed, Asif
    Samue, Maria
    Zhao, Wei
    Bonnycastle, Lori L.
    Jackson, Anne U.
    Narisu, Narisu
    Swift, Amy J.
    Southam, Lorraine
    Marten, Jonathan
    Huyghe, Jeroen R.
    Stancakova, Alena
    Fava, Cristiano
    Ohlsson, Therese
    Matchan, Angela
    Stirrups, Kathleen E.
    Bork-Jensen, Jette
    Gjesing, Anette P.
    Kontto, Jukka
    Perola, Markus
    Shaw-Hawkins, Susan
    Havulinna, Aki S.
    Zhang, He
    Donnelly, Louise A.
    Groves, Christopher J.
    Rayner, N. William
    Neville, Matt J.
    Robertson, Neil R.
    Yiorkas, Andrianos M.
    Herzig, Karl-Heinz
    Kajantie, Eero
    Zhang, Weihua
    Willems, Sara M.
    Lannfelt, Lars
    Malerba, Giovanni
    Soranzo, Nicole
    Trabetti, Elisabetta
    Verweij, Niek
    Evangelou, Evangelos
    Moayyeri, Alireza
    Vergnaud, Anne-Claire
    Nelson, Christopher P.
    Poveda, Alaitz
    Varga, Tibor V.
    Caslake, Muriel
    de Craen, Anton J. M.
    Trompet, Stella
    Luan, Jian'an
    Scott, Robert A.
    Harris, Sarah E.
    Liewald, David C. M.
    Marioni, Riccardo
    Menni, Cristina
    Farmaki, Aliki-Eleni
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Huffman, Jennifer E.
    Hassinen, Maija
    Burgess, Stephen
    Vasan, Ramachandran S.
    Felix, Janine F.
    Uria-Nickelsen, Maria
    Malarstign, Anders
    Reilly, Dermot F.
    Hoek, Maarten
    Vogt, Thomas F.
    Lin, Honghuang
    Lieb, Wolfgang
    Traylor, Matthew
    Markus, Hugh S.
    Highland, Heather M.
    Justice, Anne E.
    Marouli, Eirini
    Lindstrom, Jaana
    Uusitupa, Matti
    Komulainen, Pirjo
    Lakka, Timo A.
    Rauramaa, Rainer
    Polasek, Ozren
    Rudan, Igor
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    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 School of Public Health, Boston, Massachusetts, USA.
    Dedoussis, George
    Spector, Timothy D.
    Jousilahti, Pekka
    Mannisto, Satu
    Deary, Ian J.
    Starr, John M.
    Langenberg, Claudia
    Wareham, Nick J.
    Brown, Morris J.
    Dominiczak, Anna F.
    Connell, John M.
    Jukema, J. Wouter
    Sattar, Naveed
    Ford, Ian
    Packard, Chris J.
    Esko, Tonu
    Magi, Reedik
    Metspalu, Andres
    de Boer, Rudolf A.
    van der Meer, Peter
    van der Harst, Pim
    Gambaro, Giovanni
    Ingelsson, Erik
    Lind, Lars
    de Bakker, Paul I. W.
    Numans, Mattijs E.
    Brandslund, Ivan
    Christensen, Cramer
    Petersen, Eva R. B.
    Korpi-Hyovalti, Eeva
    Oksa, Heikki
    Chambers, John C.
    Kooner, Jaspal S.
    Blakemore, Alexandra I. F.
    Franks, Steve
    Jarvelin, Marjo-Riitta
    Husemoen, Lise L.
    Linneberg, Allan
    Skaaby, Tea
    Thuesen, Betina
    Karpe, Fredrik
    Tuomilehto, Jaakko
    Doney, Alex S. F.
    Morris, Andrew D.
    Palmer, Colin N. A.
    Holmen, Oddgeir Lingaas
    Hveem, Kristian
    Willer, Cristen J.
    Tuomi, Tiinamaija
    Groop, Leif
    Karajamaki, AnneMari
    Palotie, Aarno
    Ripatti, Samuli
    Salomaa, Veikko
    Alam, Dewan S.
    Majmnder, Abdulla Al Shafi
    Di Angelantonio, Emanuele
    Chowdhury, Rajiv
    McCarthy, Mark I.
    Poulter, Neil
    Stanton, Alice V.
    Sever, Peter
    Amouyel, Philippe
    Arveiler, Dominique
    Blankenberg, Stefan
    Ferrieres, Jean
    Kee, Frank
    Kuulasmaa, Kari
    Muller-Nurasyid, Martina
    Veronesi, Giovanni
    Virtamo, Jarmo
    Deloukas, Panos
    Elliott, Paul
    Zeggini, Eleftheria
    Kathiresan, Sekar
    Melander, Olle
    Kuusisto, Johanna
    Laakso, Markku
    Padmanabhan, Sandosh
    Porteous, David J.
    Hayward, Caroline
    Scotland, Generation
    Collins, Francis S.
    Mohlke, Karen L.
    Hansen, Torben
    Pedersen, Oluf
    Boehnke, Michael
    Stringham, Heather M.
    Frossard, Philippe
    Newton-Cheh, Christopher
    Tobin, Martin D.
    Nordestgaard, Borge Gronne
    Caulfield, Mark J.
    Mahajan, Anubha
    Morris, Andrew P.
    Tomaszewski, Maciej
    Samani, Nilesh J.
    Saleheen, Danish
    Asselbergs, Folkert W.
    Lindgren, Cecilia M.
    Danesh, John
    Wain, Louise V.
    Butterworth, Adam S.
    Howson, Joanna M. M.
    Munroe, Patricia B.
    Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 10, p. 1151-1161Article in journal (Refereed)
    Abstract [en]

    High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low frequency and common genetic variants in up to 192,763 individuals and used similar to 155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

  • 254. Takahashi, Hannah
    et al.
    Cornish, Alex J.
    Sud, Amit
    Law, Philip J.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina N.
    Claus, Elizabeth B.
    Il'yasova, Dora
    Schildkraut, Joellen
    Barnholtz-Sloan, Jill S.
    Olson, Sara H.
    Bernstein, Jonine L.
    Lai, Rose K.
    Schoemaker, Minouk J.
    Simon, Matthias
    Hoffmann, Per
    Nöthen, Markus M.
    Joeckel, Karl-Heinz
    Chanock, Stephen
    Rajaraman, Preetha
    Johansen, Christoffer
    Jenkins, Robert B.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wrensch, Margaret R.
    Sanson, Marc
    Bondy, Melissa L.
    Turnbull, Clare
    Houlston, Richard S.
    Mendelian randomisation study of the relationship between vitamin D and risk of glioma2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2339Article in journal (Refereed)
    Abstract [en]

    To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH) D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH) D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH) D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH) D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH) D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH) D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH) D levels and risk of GBM.

  • 255. Tanaka, Toshiko
    et al.
    Ngwa, Julius S.
    van Rooij, Frank J. A.
    Zillikens, M. Carola
    Wojczynski, Mary K.
    Frazier-Wood, Alexis C.
    Houston, Denise K.
    Kanoni, Stavroula
    Lemaitre, Rozenn N.
    Luan, Jian'an
    Mikkila, Vera
    Renstrom, Frida
    Sonestedt, Emily
    Zhao, Jing Hua
    Chu, Audrey Y.
    Qi, Lu
    Chasman, Daniel I.
    Otto, Marcia C. de Oliveira
    Dhurandhar, Emily J.
    Feitosa, Mary F.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Khaw, Kay-Tee
    Lohman, Kurt K.
    Manichaikul, Ani
    McKeown, Nicola M.
    Mozaffarian, Dariush
    Singleton, Andrew
    Stirrups, Kathleen
    Viikari, Jorma
    Ye, Zheng
    Bandinelli, Stefania
    Barroso, Ines
    Deloukas, Panos
    Forouhi, Nita G.
    Hofman, Albert
    Liu, Yongmei
    Lyytikainen, Leo-Pekka
    North, Kari E.
    Dimitriou, Maria
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Kahonen, Mika
    Langenberg, Claudia
    Ordovas, Jose M.
    Uitterlinden, Andre G.
    Hu, Frank B.
    Kalafati, Ioanna-Panagiota
    Raitakari, Olli
    Franco, Oscar H.
    Johnson, Andrew
    Emilsson, Valur
    Schrack, Jennifer A.
    Semba, Richard D.
    Siscovick, David S.
    Arnett, Donna K.
    Borecki, Ingrid B.
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kritchevsky, Stephen B.
    Lehtimaki, Terho
    Loos, Ruth J. F.
    Orho-Melander, Marju
    Rotter, Jerome I.
    Wareham, Nicholas J.
    Witteman, Jacqueline C. M.
    Ferrucci, Luigi
    Dedoussis, George
    Cupples, L. Adrienne
    Nettleton, Jennifer A.
    Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake2013In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 97, no 6, p. 1395-1402Article in journal (Refereed)
    Abstract [en]

    Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

    Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

    Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 x 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n 7724) provided additional replication data.

    Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (beta +/- SE: 0.25 +/- 0.04%; P = 1.68 x 10(-8)) and lower fat (beta = SE: -0.21 +/- 0.04%; P = 1.57 x 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI) increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (beta +/- SE: 0.10 +/- 0.02%; P = 9.96 x 10(-10)), independent of BMI (after adjustment for BMI, beta +/- SE: 0.08 +/- 0.02%; P = 3.15 x 10(-7)).

    Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

  • 256. Teerlink, Craig C.
    et al.
    Thibodeau, Stephen N.
    McDonnell, Shannon K.
    Schaid, Daniel J.
    Rinckleb, Antje
    Maier, Christiane
    Vogel, Walther
    Cancel-Tassin, Geraldine
    Egrot, Christophe
    Cussenot, Olivier
    Foulkes, William D.
    Giles, Graham G.
    Hopper, John L.
    Severi, Gianluca
    Eeles, Ros
    Easton, Douglas
    Kote-Jarai, Zsofia
    Guy, Michelle
    Cooney, Kathleen A.
    Ray, Anna M.
    Zuhlke, Kimberly A.
    Lange, Ethan M.
    FitzGerald, Liesel M.
    Stanford, Janet L.
    Ostrander, Elaine A.
    Wiley, Kathleen E.
    Isaacs, Sarah D.
    Walsh, Patrick C.
    Isaacs, William B.
    Wahlfors, Tiina
    Tammela, Teuvo
    Schleutker, Johanna
    Wiklund, Fredrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Grönberg, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Carpten, John
    Bailey-Wilson, Joan
    Whittemore, Alice S.
    Oakley-Girvan, Ingrid
    Hsieh, Chih-Lin
    Catalona, William J.
    Zheng, S. Lilly
    Jin, Guangfu
    Lu, Lingyi
    Xu, Jianfeng
    Camp, Nicola J.
    Cannon-Albright, Lisa A.
    Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease2014In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 133, no 3, p. 347-356Article in journal (Refereed)
    Abstract [en]

    Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p a parts per thousand currency sign 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

  • 257. Thorgeirsson, T. E.
    et al.
    Steinberg, S.
    Reginsson, G. W.
    Bjornsdottir, G.
    Rafnar, T.
    Jonsdottir, I.
    Helgadottir, A.
    Gretarsdottir, S.
    Helgadottir, H.
    Jonsson, S.
    Matthiasson, S. E.
    Gislason, T.
    Tyrfingsson, T.
    Gudbjartsson, T.
    Isaksson, H. J.
    Hardardottir, H.
    Sigvaldason, A.
    Kiemeney, L. A.
    Haugen, A.
    Zienolddiny, S.
    Wolf, H. J.
    Franklin, W. A.
    Panadero, A.
    Mayordomo, J. I.
    Hall, I. P.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. The OLIN studies, Department of Medicine, Sunderby Central Hospital of Norrbotten, Luleå, Sweden.
    Lundback, B.
    Dirksen, A.
    Ashraf, H.
    Pedersen, J. H.
    Masson, G.
    Sulem, P.
    Thorsteinsdottir, U.
    Gudbjartsson, D. F.
    Stefansson, K.
    A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 5, p. 594-600Article in journal (Refereed)
    Abstract [en]

    Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

  • 258. Trotta, Luca
    et al.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Taskinen, Mervi
    Beziat, Vivien
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wartiovaara-Kautto, Ulla
    Valimaa, Hannamari
    Jahnukainen, Kirsi
    Casanova, Jean-Laurent
    Seppanen, Mikko
    Saarela, Janna
    Koskenvuo, Minna
    Martelius, Timi
    Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders2018In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 13, article id 139Article in journal (Refereed)
    Abstract [en]

    Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKQ, the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.

    Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.

    Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.

    Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

  • 259. Turcot, Valerie
    et al.
    Lu, Yingchang
    Highland, Heather M.
    Schurmann, Claudia
    Justice, Anne E.
    Fine, Rebecca S.
    Bradfield, Jonathan P.
    Esko, Tonu
    Giri, Ayush
    Graff, Mariaelisa
    Guo, Xiuqing
    Hendricks, Audrey E.
    Karaderi, Tugce
    Lempradl, Adelheid
    Locke, Adam E.
    Mahajan, Anubha
    Marouli, Eirini
    Sivapalaratnam, Suthesh
    Young, Kristin L.
    Alfred, Tamuno
    Feitosa, Mary F.
    Masca, Nicholas G. D.
    Manning, Alisa K.
    Medina-Gomez, Carolina
    Mudgal, Poorva
    Ng, Maggie C. Y.
    Reiner, Alex P.
    Vedantam, Sailaja
    Willems, Sara M.
    Winkler, Thomas W.
    Abecasis, Goncalo
    Aben, Katja K.
    Alam, Dewan S.
    Alharthi, Sameer E.
    Allison, Matthew
    Amouyel, Philippe
    Asselbergs, Folkert W.
    Auer, Paul L.
    Balkau, Beverley
    Bang, Lia E.
    Barroso, Ines
    Bastarache, Lisa
    Benn, Marianne
    Bergmann, Sven
    Bielak, Lawrence F.
    Blueher, Matthias
    Boehnke, Michael
    Boeing, Heiner
    Boerwinkle, Eric
    Boeger, Carsten A.
    Bork-Jensen, Jette
    Bots, Michiel L.
    Bottinger, Erwin P.
    Bowden, Donald W.
    Brandslund, Ivan
    Breen, Gerome
    Brilliant, Murray H.
    Broer, Linda
    Brumat, Marco
    Burt, Amber A.
    Butterworth, Adam S.
    Campbell, Peter T.
    Cappellani, Stefania
    Carey, David J.
    Catamo, Eulalia
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Chen, Yii-Der I.
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audrey Y.
    Cocca, Massimiliano
    Collins, Francis S.
    Cook, James P.
    Corley, Janie
    Galbany, Jordi Corominas
    Cox, Amanda J.
    Crosslin, David S.
    Cuellar-Partida, Gabriel
    D'Eustacchio, Angela
    Danesh, John
    Davies, Gail
    Bakker, Paul I. W.
    Groot, Mark C. H.
    Mutsert, Renee
    Deary, Ian J.
    Dedoussis, George
    Demerath, Ellen W.
    Heijer, Martin
    Hollander, Anneke I.
    Ruijter, Hester M.
    Dennis, Joe G.
    Denny, Josh C.
    Angelantonio, Emanuele
    Drenos, Fotios
    Du, Mengmeng
    Dube, Marie-Pierre
    Dunning, Alison M.
    Easton, Douglas F.
    Edwards, Todd L.
    Ellinghaus, David
    Ellinor, Patrick T.
    Elliott, Paul
    Evangelou, Evangelos
    Farmaki, Aliki-Eleni
    Farooqi, I. Sadaf
    Faul, Jessica D.
    Fauser, Sascha
    Feng, Shuang
    Ferrannini, Ele
    Ferrieres, Jean
    Florez, Jose C.
    Ford, Ian
    Fornage, Myriam
    Franco, Oscar H.
    Franke, Andre
    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 School of Public Health, Boston, MA, USA.
    Friedrich, Nele
    Frikke-Schmidt, Ruth
    Galesloot, Tessel E.
    Gan, Wei
    Gandin, Ilaria
    Gasparini, Paolo
    Gibson, Jane
    Giedraitis, Vilmantas
    Gjesing, Anette P.
    Gordon-Larsen, Penny
    Gorski, Mathias
    Grabe, Hans-Joergen
    Grant, Struan F. A.
    Grarup, Niels
    Griffiths, Helen L.
    Grove, Megan L.
    Gudnason, Vilmundur
    Gustafsson, Stefan
    Haessler, Jeff
    Hakonarson, Hakon
    Hammerschlag, Anke R.
    Hansen, Torben
    Harris, Kathleen Mullan
    Harris, Tamara B.
    Hattersley, Andrew T.
    Have, Christian T.
    Hayward, Caroline
    He, Liang
    Heard-Costa, Nancy L.
    Heath, Andrew C.
    Heid, Iris M.
    Helgeland, Oyvind
    Hernesniemi, Jussi
    Hewitt, Alex W.
    Holmen, Oddgeir L.
    Hovingh, G. Kees
    Howson, Joanna M. M.
    Hu, Yao
    Huang, Paul L.
    Huffman, Jennifer E.
    Ikram, M. Arfan
    Ingelsson, Erik
    Jackson, Anne U.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Research Unit Skellefteå, Skellefteå, Sweden.
    Jarvik, Gail P.
    Jensen, Gorm B.
    Jia, Yucheng
    Johansson, Stefan
    Jorgensen, Marit E.
    Jorgensen, Torben
    Jukema, J. Wouter
    Kahali, Bratati
    Kahn, Rene S.
    Kahonen, Mika
    Kamstrup, Pia R.
    Kanoni, Stavroula
    Kaprio, Jaakko
    Karaleftheri, Maria
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kathiresan, Sekar
    Kee, Frank
    Kiemeney, Lambertus A.
    Kim, Eric
    Kitajima, Hidetoshi
    Komulainen, Pirjo
    Kooner, Jaspal S.
    Kooperberg, Charles
    Korhonen, Tellervo
    Kovacs, Peter
    Kuivaniemi, Helena
    Kutalik, Zoltan
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laakso, Markku
    Lakka, Timo A.
    Lamparter, David
    Lange, Ethan M.
    Lange, Leslie A.
    Langenberg, Claudia
    Larson, Eric B.
    Lee, Nanette R.
    Lehtimaki, Terho
    Lewis, Cora E.
    Li, Huaixing
    Li, Jin
    Li-Gao, Ruifang
    Lin, Honghuang
    Lin, Keng-Hung
    Lin, Li-An
    Lin, Xu
    Lind, Lars
    Lindstrom, Jaana
    Linneberg, Allan
    Liu, Ching-Ti
    Liu, Dajiang J.
    Liu, Yongmei
    Lo, Ken S.
    Lophatananon, Artitaya
    Lotery, Andrew J.
    Loukola, Anu
    Luan, Jian'an
    Lubitz, Steven A.
    Lyytikainen, Leo-Pekka
    Mannisto, Satu
    Marenne, Gaelle
    Mazul, Angela L.
    McCarthy, Mark I.
    McKean-Cowdin, Roberta
    Medland, Sarah E.
    Meidtner, Karina
    Milani, Lili
    Mistry, Vanisha
    Mitchell, Paul
    Mohlke, Karen L.
    Moilanen, Leena
    Moitry, Marie
    Montgomery, Grant W.
    Mook-Kanamori, Dennis O.
    Moore, Carmel
    Mori, Trevor A.
    Morris, Andrew D.
    Morris, Andrew P.
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Nalls, Mike A.
    Narisu, Narisu
    Nelson, Christopher P.
    Neville, Matt
    Nielsen, Sune F.
    Nikus, Kjell
    Njolstad, Pal R.
    Nordestgaard, Borge G.
    Nyholt, Dale R.
    O'Connel, Jeffrey R.
    O'Donoghue, Michelle L.
    Loohuis, Loes M. Olde
    Ophoff, Roel A.
    Owen, Katharine R.
    Packard, Chris J.
    Padmanabhan, Sandosh
    Palmer, Colin N. A.
    Palmer, Nicholette D.
    Pasterkamp, Gerard
    Patel, Aniruddh P.
    Pattie, Alison
    Pedersen, Oluf
    Peissig, Peggy L.
    Peloso, Gina M.
    Pennell, Craig E.
    Perola, Markus
    Perry, James A.
    Perry, John R. B.
    Pers, Tune H.
    Person, Thomas N.
    Peters, Annette
    Petersen, Eva R. B.
    Peyser, Patricia A.
    Pirie, Ailith
    Polasek, Ozren
    Polderman, Tinca J.
    Puolijoki, Hannu
    Raitakari, Olli T.
    Rasheed, Asif
    Rauramaa, Rainer
    Reilly, Dermot F.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rheinberger, Myriam
    Ridker, Paul M.
    Rioux, John D.
    Rivas, Manuel A.
    Roberts, David J.
    Robertson, Neil R.
    Robino, Antonietta
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Rudan, Igor
    Ruth, Katherine S.
    Saleheen, Danish
    Salomaa, Veikko
    Samani, Nilesh J.
    Sapkota, Yadav
    Sattar, Naveed
    Schoen, Robert E.
    Schreiner, Pamela J.
    Schulze, Matthias B.
    Scott, Robert A.
    Segura-Lepe, Marcelo P.
    Shah, Svati H.
    Sheu, Wayne H. -H.
    Sim, Xueling
    Slater, Andrew J.
    Small, Kerrin S.
    Smith, Albert V.
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Starr, John M.
    Stefansson, Kari
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen E.
    Strauch, Konstantin
    Stringham, Heather M.
    Stumvoll, Michael
    Sun, Liang
    Surendran, Praveen
    Swift, Amy J.
    Tada, Hayato
    Tansey, Katherine E.
    Tardif, Jean-Claude
    Taylor, Kent D.
    Teumer, Alexander
    Thompson, Deborah J.
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Thuesen, Betina H.
    Toenjes, Anke
    Tromp, Gerard
    Trompet, Stella
    Tsafantakis, Emmanouil
    Tuomilehto, Jaakko
    Tybjaerg-Hansen, Anne
    Tyrer, Jonathan P.
    Uher, Rudolf
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Laan, Sander W.
    Duijn, Cornelia M.
    Leeuwen, Nienke
    van Setten, Jessica
    Vanhala, Mauno
    Varbo, Anette
    Varga, Tibor V.
    Varma, Rohit
    Edwards, Digna R. Velez
    Vermeulen, Sita H.
    Veronesi, Giovanni
    Vestergaard, Henrik
    Vitart, Veronique
    Vogt, Thomas F.
    Voelker, Uwe
    Vuckovic, Dragana
    Wagenknecht, Lynne E.
    Walker, Mark
    Wallentin, Lars
    Wang, Feijie
    Wang, Carol A.
    Wang, Shuai
    Wang, Yiqin
    Ware, Erin B.
    Wareham, Nicholas J.
    Warren, Helen R.
    Waterworth, Dawn M.
    Wessel, Jennifer
    White, Harvey D.
    Willer, Cristen J.
    Wilson, James G.
    Witte, Daniel R.
    Wood, Andrew R.
    Wu, Ying
    Yaghootkar, Hanieh
    Yao, Jie
    Yao, Pang
    Yerges-Armstrong, Laura M.
    Young, Robin
    Zeggini, Eleftheria
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Jing Hua
    Zhao, Wei
    Zhou, Wei
    Zondervan, Krina T.
    Rotter, Jerome I.
    Pospisilik, John A.
    Rivadeneira, Fernando
    Borecki, Ingrid B.
    Deloukas, Panos
    Frayling, Timothy M.
    Lettre, Guillaume
    North, Kari E.
    Lindgren, Cecilia M.
    Hirschhorn, Joel N.
    Loos, Ruth J. F.
    Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 1, p. 26-41Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

  • 260. Ueda, Yasutaka
    et al.
    Calado, Rodrigo T.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kajigaya, Sachiko
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hellstrom-Lindberg, Eva
    Young, Neal S.
    A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome2014In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 15, p. 68-Article in journal (Refereed)
    Abstract [en]

    Background: Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. Case presentation: A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. Conclusion: We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.

  • 261. Valencia, Liliana
    et al.
    Randazzo, Andres
    Engfeldt, Peter
    Olsson, Lovisa A.
    Chavez, Adolfo
    Buckland, Robert J.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Almon, Ricardo
    Identification of novel genetic variants in the mutational hotspot region 14kb upstream of the LCT gene in a Mexican population2017In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 77, no 5, p. 311-314Article in journal (Refereed)
    Abstract [en]

    Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (approximate to 14kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT -13910C>T, several others are found in East Africans and Arabs, e.g. LCT -13907C>G and LCT -13915T>G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501bp region spanning the LCT -13910C>T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT -13910T-allele was q=0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT -13910T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.

  • 262. Van Den Bogaert, Ann
    et al.
    Sleegers, Kristel
    De Zutter, Sonia
    Heyrman, Lien
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Van Broeckhoven, Christine
    Del-Favero, Jurgen
    No allelic association or interaction of three known functional polymorphisms with bipolar disorder in a northern Swedish isolated population2006In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 16, no 5, p. 209-212Article in journal (Refereed)
    Abstract [en]

    Most genetic association studies in bipolar disorder have focussed on genes involved in major neurotransmitter systems or brain development. Functional polymorphisms in the serotonin transporter (5-HTTLPR), catechol-O-methyltransferase (Val158Met) and dopamine D3 receptor (Ser9Gly) genes have all been associated with bipolar disorder. We aimed at investigating whether these functional variants contribute to the genetic etiology of bipolar disorder in a northern Swedish isolated population. Moreover, we wanted to gain information about the synergistic contribution of these functional variants. Neither of these functional polymorphisms was associated with bipolar disorder in the northern Swedish patient-control sample nor did we find evidence of gene-gene interaction. Together, our data suggest that these functional variants are not involved in the etiology of bipolar disorder in the northern Swedish population nor did gene-gene interaction analysis support a central role of these variants in bipolar disorder.

  • 263.
    Van Den Eede, Filip
    et al.
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology ; Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp ; Department of Psychiatry, University Hospital Antwerp, Edegem.
    Venken, Tine
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Van Den Bogaert, Ann
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Del-Favero, Jurgen
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Psychology, Stockholm University, Stockholm, Sweden.
    Van Broeckhoven, Christine
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology.
    Claes, Stephan J
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology ; Department of Psychiatry, University Hospital Gasthuisberg, Leuven, Belgium.
    Single nucleotide polymorphism analysis of corticotropin-releasing factor-binding protein gene in bipolar disorder2007In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 17, no 5, p. 304-307Article in journal (Refereed)
    Abstract [en]

    Corticotropin-releasing factor-binding protein regulates the availability of free corticotropin-releasing factor and is a functional candidate gene for affective disorders. The aim of this study was to examine the association between polymorphisms in CRF-BP gene and bipolar disorder in an isolated Swedish population. One hundred and eighty-two patients with bipolar I disorder and 333 controls from Northern Sweden were included in the study. Five single nucleotide polymorphisms and a deletion polymorphism in the CRF-BP gene were genotyped. The haplotype block structure of the gene was considered and the expectation maximization algorithm was adopted to estimate the haplotype frequencies. As a result, there were no significant associations of the different polymorphisms in the CRF-BP gene with bipolar disorder. In conclusion, this study in an isolated Swedish population does not support a role for the CRF-BP gene in the vulnerability for bipolar disorder.

  • 264.
    van Dijk-Härd, Iris
    et al.
    Division for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Feld, Sari
    ivision for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundkvist, Inger
    Division for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Age-related impaired affinity maturation and differential D-JH gene usage in human VH6-expressing B lymphocytes from healthy individuals1997In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 27, no 6, p. 1381-1386Article in journal (Refereed)
    Abstract [en]

    To elucidate the basic molecular events underlying humoral immunity during ontogeny and senescence, we analyzed a panel of 179 polymerase chain reaction-derived VH6-D-JH rearrangements from cord blood, peripheral blood, and spleen. Nucleotide sequence analysis of the CDR3 region shows that there is a difference in D and JH gene usage in functional rearrangements between lymphocytes from peripheral blood and spleen. Analysis of the VH6 gene shows that the mutational frequencies rise from 0.81% in cord blood to 1.96% in peripheral blood lymphocytes derived from young adults, and decrease to 0.80% in samples from individuals older than 50 years. The number of rearrangements carrying mutations follows a similar pattern: 22% in cord blood, 73% in the age group 20-49 years, and 57% in the age group over 50 years. The mutational frequencies among the mutated genes are, however, similar for cord blood and young adults, 2.76% and 2.51%, respectively, and 1.3% in older adults. These data show an age-related impaired affinity maturation which might relate to the decrease in immunological responsiveness among the elderly.

  • 265. van Doormaal, Perry T. C.
    et al.
    Ticozzi, Nicola
    Weishaupt, Jochen H.
    Kenna, Kevin
    Diekstra, Frank P.
    Verde, Federico
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dekker, Annelot M.
    Tiloca, Cinzia
    Marroquin, Nicolai
    Overste, Daniel J.
    Pensato, Viviana
    Nuernberg, Peter
    Pulit, Sara L.
    Schellevis, Raymond D.
    Calini, Daniela
    Altmueller, Janine
    Francioli, Laurent C.
    Muller, Bernard
    Castellotti, Barbara
    Motameny, Susanne
    Ratti, Antonia
    Wolf, Joachim
    Gellera, Cinzia
    Ludolph, Albert C.
    van den Berg, Leonard H.
    Kubisch, Christian
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Volk, Alexander E.
    The role of de novo mutations in the development of amyotrophic lateral sclerosis2017In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, no 11, p. 1534-1541Article in journal (Refereed)
    Abstract [en]

    The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 x 10(-15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

  • 266. van Rheenen, Wouter
    et al.
    Shatunov, Aleksey
    Dekker, Annelot M.
    McLaughlin, Russell L.
    Diekstra, Frank P.
    Pulit, Sara L.
    van der Spek, Rick A. A.
    Vosa, Urmo
    de Jong, Simone
    Robinson, Matthew R.
    Yang, Jian
    Fogh, Isabella
    van Doormaal, Perry T. C.
    Tazelaar, Gijs H. P.
    Koppers, Max
    Blokhuis, Anna M.
    Sproviero, William
    Jones, Ashley R.
    Kenna, Kevin P.
    van Eijk, Kristel R.
    Harschnitz, Oliver
    Schellevis, Raymond D.
    Brands, William J.
    Medic, Jelena
    Menelaou, Androniki
    Vajda, Alice
    Ticozzi, Nicola
    Lin, Kuang
    Rogelj, Boris
    Vrabec, Katarina
    Ravnik-Glavac, Metka
    Koritnik, Blazi
    Zidar, Janez
    Leonardis, Lea
    Groselj, Leja Dolenc
    Millecamps, Stephanie
    Salachas, Francois
    Meininger, Vincent
    de Carvalho, Mamede
    Pinto, Susana
    Mora, Jesus S.
    Rojas-Garcia, Ricardo
    Polak, Meraida
    Chandran, Siddharthan
    Colville, Shuna
    Swingler, Robert
    Morrison, Karen E.
    Shaw, Pamela J.
    Hardy, John
    Orrell, Richard W.
    Pittman, Alan
    Sidle, Katie
    Fratta, Pietro
    Malaspina, Andrea
    Topp, Simon
    Petri, Susanne
    Abdulla, Susanne
    Drepper, Carsten
    Sendtner, Michael
    Meyer, Thomas
    Ophoff, Roel A.
    Staats, Kim A.
    Wiedau-Pazos, Martina
    Lomen-Hoerth, Catherine
    Van Deerlin, Vivianna M.
    Trojanowski, John Q.
    Elman, Lauren
    McCluskey, Leo
    Basak, A. Nazli
    Tunca, Ceren
    Hamzeiy, Hamid
    Parman, Yesim
    Meitinger, Thomas
    Lichtner, Peter
    Radivojkov-Blagojevic, Milena
    Andres, Christian R.
    Maurel, Cindy
    Bensimon, Gilbert
    Landwehrmeyer, Bernhard
    Brice, Alexis
    Payan, Christine A. M.
    Saker-Delye, Safaa
    Duerr, Alexandra
    Wood, Nicholas W.
    Tittmann, Lukas
    Lieb, Wolfgang
    Franke, Andre
    Rietschel, Marcella
    Cichon, Sven
    Noethen, Markus M.
    Amouyel, Philippe
    Tzourio, Christophe
    Dartigues, Jean-Francois
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Estrada, Karol
    Hofman, Albert
    Curtis, Charles
    Blauw, Hylke M.
    van der Kooi, Anneke J.
    de Visser, Marianne
    Goris, An
    Weber, Markus
    Shaw, Christopher E.
    Smith, Bradley N.
    Pansarasa, Orietta
    Cereda, Cristina
    Del Bo, Roberto
    Comi, Giacomo P.
    D'Alfonso, Sandra
    Bertolin, Cinzia
    Soraru, Gianni
    Mazzini, Letizia
    Pensato, Viviana
    Gellera, Cinzia
    Tiloca, Cinzia
    Ratti, Antonia
    Calvo, Andrea
    Moglia, Cristina
    Brunetti, Maura
    Arcuti, Simona
    Capozzo, Rosa
    Zecca, Chiara
    Lunetta, Christian
    Penco, Silvana
    Riva, Nilo
    Padovani, Alessandro
    Filosto, Massimiliano
    Muller, Bernard
    Stuit, Robbert Jan
    Blair, Ian
    Zhang, Katharine
    McCann, Emily P.
    Fifita, Jennifer A.
    Nicholson, Garth A.
    Rowe, Dominic B.
    Pamphlett, Roger
    Kiernan, Matthew C.
    Grosskreutz, Julian
    Witte, Otto W.
    Ringer, Thomas
    Prell, Tino
    Stubendorff, Beatrice
    Kurth, Ingo
    Huebner, Christian A.
    Leigh, P. Nigel
    Casale, Federico
    Chio, Adrian
    Beghi, Ettore
    Pupillo, Elisabetta
    Tortelli, Rosanna
    Logroscino, Giancarlo
    Powell, John
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Robberecht, Wim
    Van Damme, Philip
    Franke, Lude
    Pers, Tune H.
    Brown, Robert H.
    Glass, Jonathan D.
    Landers, John E.
    Hardiman, Orla
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany.
    Corcia, Philippe
    Vourc'h, Patrick
    Silani, Vincenzo
    Wray, Naomi R.
    Visscher, Peter M.
    de Bakker, Paul I. W.
    van Es, Michael A.
    Pasterkamp, R. Jeroen
    Lewis, Cathryn M.
    Breen, Gerome
    Al-Chalabi, Ammar
    van den Berg, Leonard H.
    Veldink, Jan H.
    Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 9, p. 1043-1048Article in journal (Refereed)
    Abstract [en]

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

  • 267. Varga, M G
    et al.
    Shaffer, C L
    Sierra, J C
    Suarez, G
    Piazuelo, M B
    Whitaker, M E
    Romero-Gallo, J
    Krishna, U S
    Delgado, A
    Gomez, M A
    Good, James A D
    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).
    Skaar, E P
    Correa, P
    Wilson, K T
    Hadjifrangiskou, M
    Peek, R M
    Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system2016In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 48, p. 6262-6269Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.

  • 268. Varga, Tibor V.
    et al.
    Sonestedt, Emily
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
    Koivula, Robert W.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Andersson Escher, Stefan
    Barroso, Ines
    Nilsson, Peter
    Melander, Olle
    Orho-Melander, Marju
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
    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, Skåne University Hospital Malmö, Malmö, Sweden ; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004388-Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (beta = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0x10(-11) for TC; beta = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0x10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (beta = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0x10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (beta = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1x10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (beta = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4x10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P <= 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

  • 269. Varga, Tibor V.
    et al.
    Winters, Alexandra H.
    Jablonski, Kathleen A.
    Horton, Edward S.
    Khare-Ranade, Prajakta
    Knowler, William C.
    Marcovina, Santica M.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Watson, Karol E.
    Goldberg, Ronald
    Florez, José C.
    Pollin, Toni I.
    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, MA.
    Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program2016In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, no 6, p. 495-503Article in journal (Refereed)
    Abstract [en]

    Background: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.

  • 270. Venken, Tine
    et al.
    Alaerts, Maaike
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Van Broeckhoven, Christine
    Del-Favero, Jurgen
    No association of the trace amine-associated receptor 6 with bipolar disorder in a northern Swedish population2006In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 16, no 1, p. 1-2Article in journal (Refereed)
  • 271. Venken, Tine
    et al.
    Claes, Stephan
    Sluijs, Samuël
    Paterson, Andrew D
    van Duijn, Cornelia
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Van Broeckhoven, Christine
    Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population2005In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 76, no 2, p. 237-248Article in journal (Refereed)
    Abstract [en]

    We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers similar to8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) greater than or equal to2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples similar to10 generations ago. In this similar to10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region.

  • 272. Verweij, Karin J. H.
    et al.
    Mosing, Miriam A.
    Ullén, Fredrik
    Madison, Guy
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Individual differences in personality masculinity-femininity: examining the effects of genes, environment, and prenatal hormone transfer2016In: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 19, no 2, p. 87-96Article in journal (Refereed)
    Abstract [en]

    Males and females score differently on some personality traits, but the underlying etiology of these differences is not well understood. This study examined genetic, environmental, and prenatal hormonal influences on individual differences in personality masculinity-femininity (M-F). We used Big-Five personality inventory data of 9,520 Swedish twins (aged 27 to 54) to create a bipolar M-F personality scale. Using biometrical twin modeling, we estimated the influence of genetic and environmental factors on individual differences in a M-F personality score. Furthermore, we tested whether prenatal hormone transfer may influence individuals' M-F scores by comparing the scores of twins with a same-sex versus those with an opposite-sex co-twin. On average, males scored 1.09 standard deviations higher than females on the created M-F scale. Around a third of the variation in M-F personality score was attributable to genetic factors, while family environmental factors had no influence. Males and females from opposite-sex pairs scored significantly more masculine (both approximately 0.1 SD) than those from same-sex pairs. In conclusion, genetic influences explain part of the individual differences in personality M-F, and hormone transfer from the male to the female twin during pregnancy may increase the level of masculinization in females. Additional well-powered studies are needed to clarify this association and determine the underlying mechanisms in both sexes.

  • 273.
    Vikberg, Ann-Louise
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Vooder, Tonu
    Lokk, Kaie
    Annilo, Tarmo
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutation analysis and copy number alterations of KIF23 in non-small-cell lung cancer exhibiting KIF23 over-expression2017In: OncoTargets and Therapy, ISSN 1178-6930, Vol. 10, p. 4969-4979Article in journal (Refereed)
    Abstract [en]

    KIF23 was recently suggested to be a potential molecular target for the treatment of lung cancer. This proposal is based on elevated expression of KIF23 in several tumors affecting breast, lung, brain, and liver, and also on the presence of KIF23 mutations in melanoma and colorectal cancer. Recently, we identified a mutation in the KIF23 gene causing a rare hereditary form of dyserythropoietic anemia (CDA III) with predisposition to blood cancer. We suggested that KIF23 overexpression in tumors might be due to the presence of activating somatic mutations, and therefore, mutation screening of the KIF23 in 15 non-small-cell lung cancer (NSCLC) cases with elevated expression level of KIF23 was undertaken. Eight sequence variants were found in all samples. Furthermore, one variant was present in two cases, and one variant was case specific. Nine variants were previously reported while one variant lacks frequency information. Nine of ten cases available for single nucleotide polymorphism-array analysis demonstrated aberrant karyotypes with additional copy of entire chromosome 15. Thus, no activating somatic mutations in coding regions of the KIF23 were found. Furthermore, no mutations were detected in cell cycle genes homology region in KIF23 promoter responsible for p53-dependent repression of KIF23 expression. We showed that the elevated level of KIF23 could be due to additional copy of chromosome 15 demonstrated in 90% of NSCLC cases analyzed in this study. Considering the crucial role of KIF23 in the final step of mitosis, the gene is a potential molecular marker, and for better understanding of its role in cancer development, more tumors should be analyzed.

  • 274. von Salomé, Jenny
    et al.
    Boonstra, Philip S.
    Karimi, Masoud
    Silander, Gustav
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Stenmark-Askmalm, Marie
    Gebre-Medhin, Samuel
    Aravidis, Christos
    Nilbert, Mef
    Lindblom, Annika
    Lagerstedt-Robinson, Kristina
    Genetic anticipation in Swedish Lynch syndrome families2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007012Article in journal (Refereed)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

  • 275. Wahlberg, Per
    et al.
    Lundmark, Anders
    Nordlund, Jessica
    Busche, Stephan
    Raine, Amanda
    Tandre, Karolina
    Rönnblom, Lars
    Sinnett, Daniel
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Pastinen, Tomi
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands2016In: Epigenomics, ISSN 1750-1911, Vol. 8, no 10, p. 1367-1387Article in journal (Refereed)
    Abstract [en]

    Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

  • 276. Wang, Chuan
    et al.
    Ahlford, Annika
    Järvinen, Tiina M
    Nordmark, Gunnel
    Eloranta, Maija-Leena
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A
    Truedsson, Lennart
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sjöwall, Christopher
    Julkunen, Heikki
    Criswell, Lindsey A
    Graham, Robert R
    Behrens, Timothy W
    Kere, Juha
    Rönnblom, Lars
    Syvänen, Ann-Christine
    Sandling, Johanna K
    Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 9, p. 994-999Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case-control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

  • 277.
    Wang, Sen
    et al.
    School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China.
    Zhao, Guanghui
    Xi'an Honghui Hospital, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Shao, Wanzhen
    School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China.
    Liu, Huan
    School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China.
    Wang, Weizhuo
    Orthopedic Department, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Wu, Cuiyan
    Orthopedic Department, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China; School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China.
    Guo, Xiong
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China; School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China.
    The importance of Se-related genes in the chondrocyte of Kashin-Beck disease revealed by whole genomic microarray and network analysis2019In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 187, no 2, p. 367-375Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is an endemic, chronic, and degenerative osteoarthropathy. Selenium (Se) deficiency plays important role in the pathogenesis of KBD. We aimed to screen Se-related gene from chondrocytes of patients with KBD. Whole-genome oligonucleotide microarrays were used to detect differentially expressed genes. qRT-PCR was used to confirm the microarray results. Comparative Toxicogenomics Database (CTD) was used to screen Se-related genes from differentially expressed genes. Gene Ontology (GO) classifications and network analysis of Se-related genes were constituted by STRING online system. Three hundred ninety-nine differentially expressed genes were obtained from microarray. Among them, 54 Se-related genes were identified by CTD. The qRT-PCR validation showed that four genes expressed similarly with the ones in the microarray transcriptional profiles. The Se-related genes were categorized into 6 cellular components, 8 molecular functions, 44 biological processes, 10 pathways, and 1 network by STRING. The Se-related gene insulin-like growth factor binding protein 2 (IGFBP2), insulin-like growth factor binding protein 3 (IGFBP3), interleukin 6 (IL6), BCL2, apoptosis regulator (BCL2), and BCL2-associated X, apoptosis regulator (BAX), which involved in many molecular functions, biological processes, and apoptosis pathway may play important roles in the pathogenesis of KBD.

  • 278.
    Wang, Shuang
    et al.
    Department of Orthodontics, Stomatological Hospital, Key Laboratory of Environment and Genes Related to Diseases, Department of Public Health, College of Medicine, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
    Guo, Xiong
    Department of Orthodontics, Stomatological Hospital, Key Laboratory of Environment and Genes Related to Diseases, Department of Public Health, College of Medicine, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
    Wu, Xiao-ming
    The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
    Lammi, Mikko J
    Department of Biosciences, University of Eastern Finland, Kuopio, Finland.
    Genome-wide gene expression analysis suggests an important role of suppressed immunity in pathogenesis of Kashin-Beck disease.2012In: PloS one, ISSN 1932-6203, Vol. 7, no 1, p. e28439-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the differences between the gene expression profiles in peripheral blood mononuclear cells (PBMC) from normal controls and patients with Kashin-Beck disease (KBD).

    METHODS: Twenty KBD patients and 12 normal subjects were selected from a KBD-endemic area and divided into four pairs of KBD vs. control (KBD, n = 5 per pair; control, n = 3 per pair). RNAs were respectively isolated from KBD PBMCs and normal PBMCs. Gene expression profiles were analyzed by oligonucleotide microarray. The gene expression profiles in PBMCs from KBD patients and normal controls were compared and the differentially expressed genes were identified. The obtained microarray data was further confirmed by using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).

    RESULTS: Approximately 501 genes, corresponding to 2.4% of the total probe transcripts, showed a 2-fold change in differential expression. 19.4% (97 out of 501)of the differentially expressed genes were commonly detected in all the four pairs. Among the 97 differentially expressed genes, 83 genes were up-regulated and 14 genes were down-regulated, compared with those in the normal controls. Some differentially expressed genes were found to be related to functions such as immunity, metabolism, apoptosis, cystoskeleton and cell movement, and extracellular matrix. The validity of our microarray data were supported by the results of qRT-PCR assay.

    CONCLUSION: Differences in the PBMC gene expression profile between the KBD patients and the normal controls exhibited a similar pattern among all the four pairs of microarrays examined, indicating that the suppressed immunity may play an important role in the pathogenesis of KBD.

  • 279. Wang, Tao
    et al.
    Moon, Jee-Young
    Wu, Yiqun
    Amos, Christopher I.
    Hung, Rayjean J.
    Tardon, Adonina
    Andrew, Angeline
    Chen, Chu
    Christiani, David C.
    Albanes, Demetrios
    van der Heijdendr, Erik H. F. M.
    Duell, Eric
    Rennert, Gadi
    Goodman, Gary
    Liu, Geoffrey
    Mckay, James D.
    Yuan, Jian-Min
    Field, John K.
    Manjer, Jonas
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kiemeney, Lambertus A.
    Le Marchand, Loic
    Teare, M. Dawn
    Schabath, Matthew B.
    Johansson, Mattias
    Aldrich, Melinda C.
    Davies, Michael
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsao, Ming-Sound
    Caporaso, Neil
    Lazarus, Philip
    Lam, Stephen
    Bojesen, Stig E.
    Arnold, Susanne
    Wu, Xifeng
    Zong, Xuchen
    Hong, Yun-Chul
    Ho, Gloria Y. F.
    Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung Cancer Consortium2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185660Article in journal (Refereed)
    Abstract [en]

    Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes.

  • 280. Wang, Zheng
    et al.
    Iida, Aritoshi
    Miyake, Noriko
    Nishiguchi, Koji M.
    Fujita, Kosuke
    Nakazawa, Toru
    Alswaid, Abdulrahman
    Albalwi, Mohammed A.
    Kim, Ok-Hwa
    Cho, Tae-Joon
    Lim, Gye-Yeon
    Isidor, Bertrand
    David, Albert
    Rustad, Cecilie F.
    Merckoll, Else
    Westvik, Jostein
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Grigelioniene, Giedre
    Kou, Ikuyo
    Nakajima, Masahiro
    Ohashi, Hirohumi
    Smithson, Sarah
    Matsumoto, Naomichi
    Nishimura, Gen
    Ikegawa, Shiro
    Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150555Article in journal (Refereed)
    Abstract [en]

    Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

  • 281. Watt, Danielle L
    et al.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Burgers, Peter M
    Kunkel, Thomas A
    Replication of ribonucleotide-containing DNA templates by yeast replicative polymerases2011In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, no 8, p. 897-902Article in journal (Refereed)
    Abstract [en]

    The major replicative DNA polymerases of S. cerevisiae (Pols α, δ, and ɛ) incorporate substantial numbers of ribonucleotides into DNA during DNA synthesis. When these ribonucleotides are not removed in vivo, they reside in the template strand used for the next round of replication and could potentially reduce replication efficiency and fidelity. To examine if the presence of ribonucleotides in a DNA template impede DNA synthesis, we determined the efficiency with which Pols α, δ, and ɛ copy DNA templates containing a single ribonucleotide. All three polymerases can replicate past ribonucleotides. Relative to all-DNA templates, bypass of ribo-containing templates is slightly reduced, to extents that depend on the identity of the ribo and the sequence context in which it resides. Bypass efficiencies for Pols δ and ɛ were increased by increasing the dNTP concentrations to those induced by cellular stress, and in the case of Pol ɛ, by inactivating the 3'-exonuclease activity. Overall, ribonucleotide bypass efficiencies are comparable to, and usually exceed, those for the common oxidative stress-induced lesion 8-oxo-guanine.

  • 282. Webb, Thomas R.
    et al.
    Erdmann, Jeanette
    Stirrups, Kathleen E.
    Stitziel, Nathan O.
    Masca, Nicholas G. D.
    Jansen, Henning
    Kanoni, Stavroula
    Nelson, Christopher P.
    Ferrario, Paola G.
    Koenig, Inke R.
    Eicher, John D.
    Johnson, Andrew D.
    Hamby, Stephen E.
    Betsholtz, Christer
    Ruusalepp, Arno
    Franzen, Oscar
    Schadt, Eric E.
    Bjoerkegren, Johan L. M.
    Weeke, Peter E.
    Auer, Paul L.
    Schick, Ursula M.
    Lu, Yingchang
    Zhang, He
    Dube, Marie-Pierre
    Goel, Anuj
    Farrall, Martin
    Peloso, Gina M.
    Won, Hong-Hee
    Do, Ron
    van Iperen, Erik
    Kruppa, Jochen
    Mahajan, Anubha
    Scott, Robert A.
    Willenborg, Christina
    Braund, Peter S.
    van Capelleveen, Julian C.
    Doney, Alex S. F.
    Donnelly, Louise A.
    Asselta, Rosanna
    Merlini, Pier A.
    Duga, Stefano
    Marziliano, Nicola
    Denny, Josh C.
    Shaffer, Christian
    El-Mokhtari, Nour Eddine
    Franke, Andre
    Heilmann, Stefanie
    Hengstenberg, Christian
    Hoffmann, Per
    Holmen, Oddgeir L.
    Hveem, Kristian
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Joeckel, Karl-Heinz
    Kessler, Thorsten
    Kriebel, Jennifer
    Laugwitz, Karl L.
    Marouli, Eirini
    Martinelli, Nicola
    McCarthy, Mark I.
    Van Zuydam, Natalie R.
    Meisinger, Christa
    Esko, Tonu
    Mihailov, Evelin
    Escher, Stefan A.
    Alver, Maris
    Moebus, Susanne
    Morris, Andrew D.
    Virtamo, Jarma
    Nikpay, Majid
    Olivieri, Oliviero
    Provost, Sylvie
    AlQarawi, Alaa
    Robertson, Neil R.
    Akinsansya, Karen O.
    Reilly, Dermot F.
    Vogt, Thomas F.
    Yin, Wu
    Asselbergs, Folkert W.
    Kooperberg, Charles
    Jackson, Rebecca D.
    Stahl, Eli
    Mueller-Nurasyid, Martina
    Strauch, Konstantin
    Varga, Tibor V.
    Waldenberger, Melanie
    Zeng, Lingyao
    Chowdhury, Rajiv
    Salomaa, Veikko
    Ford, Ian
    Jukema, J. Wouter
    Amouyel, Philippe
    Kontto, Jukka
    Nordestgaard, Borge G.
    Ferrieres, Jean
    Saleheen, Danish
    Sattar, Naveed
    Surendran, Praveen
    Wagner, Aline
    Young, Robin
    Howson, Joanna M. M.
    Butterworth, Adam S.
    Danesh, John
    Ardissino, Diego
    Bottinger, Erwin P.
    Erbel, Raimund
    Franks, Paul W.
    Girelli, Domenico
    Hall, Alistair S.
    Hovingh, G. Kees
    Kastrati, Adnan
    Lieb, Wolfgang
    Meitinger, Thomas
    Kraus, William E.
    Shah, Svati H.
    McPherson, Ruth
    Orho-Melander, Marju
    Melander, Olle
    Metspalu, Andres
    Palmer, Colin N. A.
    Peters, Annette
    Rader, Daniel J.
    Reilly, Muredach P.
    Loos, Ruth J. F.
    Reiner, Alex P.
    Roden, Dan M.
    Tardif, Jean-Claude
    Thompson, John R.
    Wareham, Nicholas J.
    Watkins, Hugh
    Willer, Cristen J.
    Samani, Nilesh J.
    Schunkert, Heribert
    Deloukas, Panos
    Kathiresan, Sekar
    Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease2017In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 69, no 7, p. 823-836Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits. CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

  • 283. Weisschuh, Nicole
    et al.
    Stingl, Katarina
    Audo, Isabelle
    Biskup, Saskia
    Bocquet, Beatrice
    Branham, Kari
    Burstedt, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    De Baere, Elfride
    De Vries, Meindert J.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Green, Andrew
    Heckenlively, John
    Leroy, Bart P.
    Meunier, Isabelle
    Traboulsi, Elias
    Wissinger, Bernd
    Kohl, Susanne
    Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia2018In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 10, p. 1366-1371Article in journal (Refereed)
    Abstract [en]

    Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic alpha'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.

  • 284. Wentzel, Christian
    et al.
    Rajcan-Separovic, Evica
    Ruivenkamp, Claudia A L
    Chantot-Bastaraud, Sandra
    Metay, Corinne
    Andrieux, Joris
    Annerén, Göran
    Gijsbers, Antoinet C J
    Druart, Luc
    Hyon, Capucine
    Portnoi, Marie-France
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Vincent-Delorme, Catherine
    Kant, Sarina G
    Steinraths, Michelle
    Marlin, Sandrine
    Giurgea, Irina
    Thuresson, Ann-Charlotte
    Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p112011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 9, p. 959-964Article in journal (Refereed)
    Abstract [en]

    With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

  • 285. Westra, Harm-Jan
    et al.
    Martinez-Bonet, Marta
    Onengut-Gumuscu, Suna
    Lee, Annette
    Luol, Yang
    Teslovich, Nikola
    Worthington, Jane
    Martin, Javier
    Huizinga, Tom
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Chen, Wei-Min
    Quinlan, Aaron
    Todd, John A.
    Eyre, Steve
    Nigrovic, Peter A.
    Regersen, Peter K. G.
    Rich, Stephen S.
    Raychaudhuri, Soumya
    Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 10, p. 1366-+Article in journal (Refereed)
    Abstract [en]

    To define potentially causal variants for autoimmune disease, we fine-mapped(1,2) 76 rheumatoid arthritis (11,475 cases,15,870 controls)(3) and type 1 diabetes loci (9,334 cases, 11,111 controls)(4). After sequencing 799 1-kilobase regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We defined credible sets of <= 5 causal variants at 5 rheumatoid arthritis and 10 type 1 diabetes loci. We identified potentially causal missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28-CTLA4, and IL2RA. We also identified potential candidate causal variants at SIRPG and TNFAIP3. Using functional assays, we confirmed allele-specific protein binding and differential enhancer activity for three variants: the CD28-CTLA4 rs117701653 SNP, MEG3 rs34552516 indel, and TNFAIP3 rs35926684 indel.

  • 286.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Loo, Peter
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lau, Ching
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e47929-Article in journal (Refereed)
    Abstract [en]

    A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

  • 287.
    Wikström, Ingela
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Molecular genetics of B- and T-lymphocyte development2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lymphocytes are essential for the generation of specific immunity. Development of B cells in the bone marrow and T cells in the thymus have several analogous features, and are tightly regulated processes. Even though there is an increasing amount of information concerning lymphopoiesis, a lot of questions remain. The aim of this thesis has been to understand some of the molecular events that contribute to the control of lymphocyte development.

    Expression of the B cell receptor is an important checkpoint in B lymphocyte development. The Dµ protein is a truncated B cell receptor that can induce some of the signals elicited by full length µ, but cannot promote further B cell differentiation. In order to determine if this could stem from an impaired survival signal, we introduced Bcl-2 into RAG2 deficient Dµ transgenic mice. Analysis of these mice showed that Dµ could not support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, data from recombination competent Dµ transgenic mice demonstrated that the Dµ induced partial block is permissive for marginal zone B cell development, whereas the formation of follicular B cells is severely reduced.

    The bHLH family of transcription factors is known to be involved in the regulation of lymphocyte development. Whereas the roles of E2A and HEB have been well documented in both B- and T-lymphocytes, detailed knowledge concerning E2-2 is lacking. To address the role of E2-2 in B cell development, we have reconstituted mice, using E2-2 deficient fetal liver cells, and analysed the B cell compartments. We also measured mRNA expression patterns for the three E-proteins in wildtype mice. Resulting data show that, in addition to a role in B cell lineage entry, E2-2 is required for efficient expansion of pro-B cells, and also influences the follicular versus marginal zone decision.

    While focusing on assigning a role for E2-2 in T-cell development, we analyzed the expression of the E-proteins during this process and performed functional studies in fetal thymic organ cultures. E2-2 deficient mouse embryos were shown to display a partial block at the DN3 stage, which was not due to proliferation or apoptosis defects. In addition, analysis of expression levels of the pre-Talpha chain suggests that E2-2 may play a role in the regulation of transcription of pre-Talpha, and therefore in the assembly of the pre-T cell receptor.

  • 288.
    Wikström, Ingela
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Penha-Goncalves, Mario
    Forssell, Johan
    Bergqvist, Ingela
    Holmberg, Dan
    A non-redundant role for the bHLH transcription factor E2-2 in early thymocyte developmentManuscript (preprint) (Other academic)
  • 289. Willems, Sara M.
    et al.
    Wright, Daniel J.
    Day, Felix R.
    Trajanoska, Katerina
    Joshi, Peter K.
    Morris, John A.
    Matteini, Amy M.
    Garton, Fleur C.
    Grarup, Niels
    Oskolkov, Nikolay
    Thalamuthu, Anbupalam
    Mangino, Massimo
    Liu, Jun
    Demirkan, Ayse
    Lek, Monkol
    Xu, Liwen
    Wang, Guan
    Oldmeadow, Christopher
    Gaulton, Kyle J.
    Lotta, Luca A.
    Miyamoto-Mikami, Eri
    Rivas, Manuel A.
    White, Tom
    Loh, Po-Ru
    Aadahl, Mette
    Amin, Najaf
    Attia, John R.
    Austin, Krista
    Benyamin, Beben
    Brage, Soren
    Cheng, Yu-Ching
    Cieszczyk, Pawel
    Derave, Wim
    Eriksson, Karl-Fredrik
    Eynon, Nir
    Linneberg, Allan
    Lucia, Alejandro
    Massidda, Myosotis
    Mitchell, Braxton D.
    Miyachi, Motohiko
    Murakami, Haruka
    Padmanabhan, Sandosh
    Pandey, Ashutosh
    Papadimitriou, Loannis
    Rajpal, Deepak K.
    Sale, Craig
    Schnurr, Theresia M.
    Sessa, Francesco
    Shrine, Nick
    Tobin, Martin D.
    Varley, Ian
    Wain, Louise V.
    Wray, Naomi R.
    Lindgren, Cecilia M.
    MacArthur, Daniel G.
    Waterworth, Dawn M.
    McCarthy, Mark I.
    Pedersen, Oluf
    Khaw, Kay-Tee
    Kie, Douglas P.
    Pitsiladis, Yannis
    Fuku, Noriyuki
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skånes University Hospital, 222 41 Lund, Sweden.
    North, Kathryn N.
    van Duijn, Cornelia M.
    Mather, Karen A.
    Hansen, Torben
    Hansson, Ola
    Spector, Tim
    Murabito, Joanne M.
    Richards, J. Brent
    Rivadeneira, Fernando
    Langenberg, Claudia
    Perry, John R. B.
    Wareham, Nick J.
    Scott, Robert A.
    Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16015Article in journal (Refereed)
    Abstract [en]

    Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 x 10(-8)) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

  • 290. Willer, Cristen J.
    et al.
    Schmidt, Ellen M.
    Sengupta, Sebanti
    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.
    Do, Ron
    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.
    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
    Kathiresan, Sekar
    Mohlke, Karen L.
    Ingelsson, Erik
    Abecasis, Goncalo R.
    Discovery and refinement of loci associated with lipid levels2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 11, p. 1274-+Article in journal (Refereed)
    Abstract [en]

    Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

  • 291. Wilson, Lauren E.
    et al.
    Xu, Zongli
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    White, Alexandra J.
    Troester, Melissa A.
    Sandler, Dale P.
    Taylor, Jack A.
    Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue2019In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 6, p. 1055-1065Article in journal (Refereed)
    Abstract [en]

    The biological mechanisms driving associations between alcohol consumption and chronic diseases might include epigenetic modification of DNA methylation. We explored the hypothesis that alcohol consumption is associated with methylation in an epigenome-wide association study of blood and normal breast tissue DNA. Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, California) array data on blood DNA methylation was examined in a discovery set of 2,878 non-Hispanic white women from the Sister Study (United States, 2004-2015) who provided detailed questionnaire information on lifetime alcohol use. Robust linear regression modeling was used to identify significant associations (false discovery rate of Q < 0.05) between the number of alcoholic drinks per week and DNA methylation at 5,458 cytosine-phosphate-guanine (CpG) sites. Associations were replicated (P < 0.05) for 677 CpGs in an independent set of 187 blood DNA samples from the Sister Study and for 628 CpGs in an independent set of 171 normal breast DNA samples; 1,207 CpGs were replicated in either blood or normal breast, with 98 CpGs replicated in both tissues. Individual gene effects were notable for phosphoglycerate dehydrogenase (PGHDH), peptidyl-prolyl cis-trans isomerase (PPIF), solute carrier 15 (SLC15), solute carrier family 43 member 1 (SLC43A1), and solute carrier family 7 member 11 (SLC7A11). We also found that high alcohol consumption was associated with significantly lower global methylation as measured by the average of CpGs on the entire array.

  • 292.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Stattin, Eva-Lena
    Westin, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Persson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jensen, Steen M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis2017In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, article id 74Article in journal (Refereed)
    Abstract [en]

    Background: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1APsequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations.

    Methods: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs.

    Results: A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males.

    Conclusions: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.

  • 293. Winkler, Thomas W
    et al.
    Justice, Anne E
    Graff, Mariaelisa
    Barata, Llilda
    Feitosa, Mary F
    Chu, Su
    Czajkowski, Jacek
    Esko, Tõnu
    Fall, Tove
    Kilpeläinen, Tuomas O
    Lu, Yingchang
    Mägi, Reedik
    Mihailov, Evelin
    Pers, Tune H
    Rüeger, Sina
    Teumer, Alexander
    Ehret, Georg B
    Ferreira, Teresa
    Heard-Costa, Nancy L
    Karjalainen, Juha
    Lagou, Vasiliki
    Mahajan, Anubha
    Neinast, Michael D
    Prokopenko, Inga
    Simino, Jeannette
    Teslovich, Tanya M
    Jansen, Rick
    Westra, Harm-Jan
    White, Charles C
    Absher, Devin
    Ahluwalia, Tarunveer S
    Ahmad, Shafqat
    Albrecht, Eva
    Alves, Alexessander Couto
    Bragg-Gresham, Jennifer L
    de Craen, Anton J M
    Bis, Joshua C
    Bonnefond, Amélie
    Boucher, Gabrielle
    Cadby, Gemma
    Cheng, Yu-Ching
    Chiang, Charleston W K
    Delgado, Graciela
    Demirkan, Ayse
    Dueker, Nicole
    Eklund, Niina
    Eiriksdottir, Gudny
    Eriksson, Joel
    Feenstra, Bjarke
    Fischer, Krista
    Frau, Francesca
    Galesloot, Tessel E
    Geller, Frank
    Goel, Anuj
    Gorski, Mathias
    Grammer, Tanja B
    Gustafsson, Stefan
    Haitjema, Saskia
    Hottenga, Jouke-Jan
    Huffman, Jennifer E
    Jackson, Anne U
    Jacobs, Kevin B
    Johansson, Åsa
    Kaakinen, Marika
    Kleber, Marcus E
    Lahti, Jari
    Mateo Leach, Irene
    Lehne, Benjamin
    Liu, Youfang
    Lo, Ken Sin
    Lorentzon, Mattias
    Luan, Jian'an
    Madden, Pamela A F
    Mangino, Massimo
    McKnight, Barbara
    Medina-Gomez, Carolina
    Monda, Keri L
    Montasser, May E
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Nolte, Ilja M
    Panoutsopoulou, Kalliope
    Pascoe, Laura
    Paternoster, Lavinia
    Rayner, Nigel W
    Renström, Frida
    Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
    Rizzi, Federica
    Rose, Lynda M
    Ryan, Kathy A
    Salo, Perttu
    Sanna, Serena
    Scharnagl, Hubert
    Shi, Jianxin
    Smith, Albert Vernon
    Southam, Lorraine
    Stančáková, Alena
    Steinthorsdottir, Valgerdur
    Strawbridge, Rona J
    Sung, Yun Ju
    Tachmazidou, Ioanna
    Tanaka, Toshiko
    Thorleifsson, Gudmar
    Trompet, Stella
    Pervjakova, Natalia
    Tyrer, Jonathan P
    Vandenput, Liesbeth
    van der Laan, Sander W
    van der Velde, Nathalie
    van Setten, Jessica
    van Vliet-Ostaptchouk, Jana V
    Verweij, Niek
    Vlachopoulou, Efthymia
    Waite, Lindsay L
    Wang, Sophie R
    Wang, Zhaoming
    Wild, Sarah H
    Willenborg, Christina
    Wilson, James F
    Wong, Andrew
    Yang, Jian
    Yengo, Loïc
    Yerges-Armstrong, Laura M
    Yu, Lei
    Zhang, Weihua
    Zhao, Jing Hua
    Andersson, Ehm A
    Bakker, Stephan J L
    Baldassarre, Damiano
    Banasik, Karina
    Barcella, Matteo
    Barlassina, Cristina
    Bellis, Claire
    Benaglio, Paola
    Blangero, John
    Blüher, Matthias
    Bonnet, Fabrice
    Bonnycastle, Lori L
    Boyd, Heather A
    Bruinenberg, Marcel
    Buchman, Aron S
    Campbell, Harry
    Chen, Yii-Der Ida
    Chines, Peter S
    Claudi-Boehm, Simone
    Cole, John
    Collins, Francis S
    de Geus, Eco J C
    de Groot, Lisette C P G M
    Dimitriou, Maria
    Duan, Jubao
    Enroth, Stefan
    Eury, Elodie
    Farmaki, Aliki-Eleni
    Forouhi, Nita G
    Friedrich, Nele
    Gejman, Pablo V
    Gigante, Bruna
    Glorioso, Nicola
    Go, Alan S
    Gottesman, Omri
    Gräßler, Jürgen
    Grallert, Harald
    Grarup, Niels
    Gu, Yu-Mei
    Broer, Linda
    Ham, Annelies C
    Hansen, Torben
    Harris, Tamara B
    Hartman, Catharina A
    Hassinen, Maija
    Hastie, Nicholas
    Hattersley, Andrew T
    Heath, Andrew C
    Henders, Anjali K
    Hernandez, Dena
    Hillege, Hans
    Holmen, Oddgeir
    Hovingh, Kees G
    Hui, Jennie
    Husemoen, Lise L
    Hutri-Kähönen, Nina
    Hysi, Pirro G
    Illig, Thomas
    De Jager, Philip L
    Jalilzadeh, Shapour
    Jørgensen, Torben
    Jukema, J Wouter
    Juonala, Markus
    Kanoni, Stavroula
    Karaleftheri, Maria
    Khaw, Kay Tee
    Kinnunen, Leena
    Kittner, Steven J
    Koenig, Wolfgang
    Kolcic, Ivana
    Kovacs, Peter
    Krarup, Nikolaj T
    Kratzer, Wolfgang
    Krüger, Janine
    Kuh, Diana
    Kumari, Meena
    Kyriakou, Theodosios
    Langenberg, Claudia
    Lannfelt, Lars
    Lanzani, Chiara
    Lotay, Vaneet
    Launer, Lenore J
    Leander, Karin
    Lindström, Jaana
    Linneberg, Allan
    Liu, Yan-Ping
    Lobbens, Stéphane
    Luben, Robert
    Lyssenko, Valeriya
    Männistö, Satu
    Magnusson, Patrik K
    McArdle, Wendy L
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Montgomery, Grant W
    Morris, Andrew P
    Narisu, Narisu
    Nelis, Mari
    Ong, Ken K
    Palotie, Aarno
    Pérusse, Louis
    Pichler, Irene
    Pilia, Maria G
    Pouta, Anneli
    Rheinberger, Myriam
    Ribel-Madsen, Rasmus
    Richards, Marcus
    Rice, Kenneth M
    Rice, Treva K
    Rivolta, Carlo
    Salomaa, Veikko
    Sanders, Alan R
    Sarzynski, Mark A
    Scholtens, Salome
    Scott, Robert A
    Scott, William R
    Sebert, Sylvain
    Sengupta, Sebanti
    Sennblad, Bengt
    Seufferlein, Thomas
    Silveira, Angela
    Slagboom, P Eline
    Smit, Jan H
    Sparsø, Thomas H
    Stirrups, Kathleen
    Stolk, Ronald P
    Stringham, Heather M
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Tan, Sian-Tsung
    Thorand, Barbara
    Tönjes, Anke
    Tremblay, Angelo
    Tsafantakis, Emmanouil
    van der Most, Peter J
    Völker, Uwe
    Vohl, Marie-Claude
    Vonk, Judith M
    Waldenberger, Melanie
    Walker, Ryan W
    Wennauer, Roman
    Widén, Elisabeth
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wright, Alan F
    Zillikens, M Carola
    van Dijk, Suzanne C
    van Schoor, Natasja M
    Asselbergs, Folkert W
    de Bakker, Paul I W
    Beckmann, Jacques S
    Beilby, John
    Bennett, David A
    Bergman, Richard N
    Bergmann, Sven
    Böger, Carsten A
    Boehm, Bernhard O
    Boerwinkle, Eric
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Chambers, John C
    Chanock, Stephen J
    Chasman, Daniel I
    Cucca, Francesco
    Cusi, Daniele
    Dedoussis, George
    Erdmann, Jeanette
    Eriksson, Johan G
    Evans, Denis A
    de Faire, Ulf
    Farrall, Martin
    Ferrucci, Luigi
    Ford, Ian
    Franke, Lude
    Franks, Paul W
    Umeå University Hospital; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America .
    Froguel, Philippe
    Gansevoort, Ron T
    Gieger, Christian
    Grönberg, Henrik
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hall, Per
    Hamsten, Anders
    van der Harst, Pim
    Hayward, Caroline
    Heliövaara, Markku
    Hengstenberg, Christian
    Hicks, Andrew A
    Hingorani, Aroon
    Hofman, Albert
    Hu, Frank
    Huikuri, Heikki V
    Hveem, Kristian
    James, Alan L
    Jordan, Joanne M
    Jula, Antti
    Kähönen, Mika
    Kajantie, Eero
    Kathiresan, Sekar
    Kiemeney, Lambertus A L M
    Kivimaki, Mika
    Knekt, Paul B
    Koistinen, Heikki A
    Kooner, Jaspal S
    Koskinen, Seppo
    Kuusisto, Johanna
    Maerz, Winfried
    Martin, Nicholas G
    Laakso, Markku
    Lakka, Timo A
    Lehtimäki, Terho
    Lettre, Guillaume
    Levinson, Douglas F
    Lind, Lars
    Lokki, Marja-Liisa
    Mäntyselkä, Pekka
    Melbye, Mads
    Metspalu, Andres
    Mitchell, Braxton D
    Moll, Frans L
    Murray, Jeffrey C
    Musk, Arthur W
    Nieminen, Markku S
    Njølstad, Inger
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Oostra, Ben A
    Palmer, Lyle J
    Pankow, James S
    Pasterkamp, Gerard
    Pedersen, Nancy L
    Pedersen, Oluf
    Penninx, Brenda W
    Perola, Markus
    Peters, Annette
    Polašek, Ozren
    Pramstaller, Peter P
    Psaty, Bruce M
    Qi, Lu
    Quertermous, Thomas
    Raitakari, Olli T
    Rankinen, Tuomo
    Rauramaa, Rainer
    Ridker, Paul M
    Rioux, John D
    Rivadeneira, Fernando
    Rotter, Jerome I
    Rudan, Igor
    den Ruijter, Hester M
    Saltevo, Juha
    Sattar, Naveed
    Schunkert, Heribert
    Schwarz, Peter E H
    Shuldiner, Alan R
    Sinisalo, Juha
    Snieder, Harold
    Sørensen, Thorkild I A
    Spector, Tim D
    Staessen, Jan A
    Stefania, Bandinelli
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tardif, Jean-Claude
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    Verbeek, André L M
    Vermeulen, Sita H
    Viikari, Jorma S
    Vitart, Veronique
    Völzke, Henry
    Vollenweider, Peter
    Waeber, Gérard
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Zeggini, Eleftheria
    Chakravarti, Aravinda
    Clegg, Deborah J
    Cupples, L Adrienne
    Gordon-Larsen, Penny
    Jaquish, Cashell E
    Rao, D C
    Abecasis, Goncalo R
    Assimes, Themistocles L
    Barroso, Inês
    Berndt, Sonja I
    Boehnke, Michael
    Deloukas, Panos
    Fox, Caroline S
    Groop, Leif C
    Hunter, David J
    Ingelsson, Erik
    Kaplan, Robert C
    McCarthy, Mark I
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Hirschhorn, Joel N
    Lindgren, Cecilia M
    Heid, Iris M
    North, Kari E
    Borecki, Ingrid B
    Kutalik, Zoltán
    Loos, Ruth J F
    The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 10, article id e1005378Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

  • 294.
    Wisten, Aase
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Boström, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutation analysis of cases of sudden unexplained death, 15 years after death: Prompt genetic evaluation after resuscitation can save future lives2012In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 83, no 10, p. 1229-1234Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of this study is to use genetic mutation analysis to determine the cause of sudden unexpected death in young (SUDY) persons with normal autopsy findings, and to provide relatives with an identified cardiac mutation with suitable cardiovascular prevention. Methods: We performed mutation analysis on blood samples from first-degree relatives of 25 cases with normal autopsy findings identified in the national Swedish study of sudden cardiac death in 15- to 35-year-olds from 1992 to 1999. Results: We found three families with long QT syndrome through mutation screening, and the mutations were verified in two of the deceased. Eight family members were found to be mutation carriers and have been provided with suitable cardiovascular prevention. Mutation screening also identified a number of common polymorphisms in the individuals screened. Clinical history revealed one family each with short QT syndrome and hypertrophic cardiomyopathy, respectively, but no mutations were found in the family members or in the deceased. Two SCDs each had occurred in two of the affected families. Conclusion: Cardiac/genetic evaluation of relatives long after SUDY can reveal a diagnosis in 5/25 (20%) of cases. Since DNA extraction of formalin fixed paraffin embedded samples is unreliable, it is important that blood or tissue samples be stored at autopsy of such cases. This can facilitate establishing a diagnosis and thereby save lives in the future. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 295. Wolpin, Brian M.
    et al.
    Rizzato, Cosmeri
    Kraft, Peter
    Kooperberg, Charles
    Petersen, Gloria M.
    Wang, Zhaoming
    Arslan, Alan A.
    Beane-Freeman, Laura
    Bracci, Paige M.
    Buring, Julie
    Canzian, Federico
    Duell, Eric J.
    Gallinger, Steven
    Giles, Graham G.
    Goodman, Gary E.
    Goodman, Phyllis J.
    Jacobs, Eric J.
    Kamineni, Aruna
    Klein, Alison P.
    Kolonel, Laurence N.
    Kulke, Matthew H.
    Li, Donghui
    Malats, Nuria
    Olson, Sara H.
    Risch, Harvey A.
    Sesso, Howard D.
    Visvanathan, Kala
    White, Emily
    Zheng, Wei
    Abnet, Christian C.
    Albanes, Demetrius
    Andreotti, Gabriella
    Austin, Melissa A.
    Barfield, Richard
    Basso, Daniela
    Berndt, Sonja I.
    Boutron-Ruault, Marie-Christine
    Brotzman, Michelle
    Buechler, Markus W.
    Bueno-de-Mesquita, H. Bas
    Bugert, Peter
    Burdette, Laurie
    Campa, Daniele
    Caporaso, Neil E.
    Capurso, Gabriele
    Chung, Charles
    Cotterchio, Michelle
    Costello, Eithne
    Elena, Joanne
    Funel, Niccola
    Gaziano, J. Michael
    Giese, Nathalia A.
    Goggins, Michael
    Gorman, Megan J.
    Gross, Myron
    Haiman, Christopher A.
    Hassan, Manal
    Helzlsouer, Kathy J.
    Henderson, Brian E.
    Holly, Elizabeth A.
    Hu, Nan
    Hunter, David J.
    Innocenti, Federico
    Jenab, Mazda
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay-Tee
    Klein, Eric A.
    Kogevinas, Manolis
    Krogh, Vittorio
    Kupcinskas, Juozas
    Kurtz, Robert C.
    LaCroix, Andrea
    Landi, Maria T.
    Landi, Stefano
    Le Marchand, Loic
    Mambrini, Andrea
    Mannisto, Satu
    Milne, Roger L.
    Nakamura, Yusuke
    Oberg, Ann L.
    Owzar, Kouros
    Patel, Alpa V.
    Peeters, Petra H. M.
    Peters, Ulrike
    Pezzilli, Raffaele
    Piepoli, Ada
    Porta, Miquel
    Real, Francisco X.
    Riboli, Elio
    Rothman, Nathaniel
    Scarpa, Aldo
    Shu, Xiao-Ou
    Silverman, Debra T.
    Soucek, Pavel
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Talar-Wojnarowska, Renata
    Taylor, Philip R.
    Theodoropoulos, George E.
    Thornquist, Mark
    Tjonneland, Anne
    Tobias, Geoffrey S.
    Trichopoulos, Dimitrios
    Vodicka, Pavel
    Wactawski-Wende, Jean
    Wentzensen, Nicolas
    Wu, Chen
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Hoover, Robert
    Hartge, Patricia
    Fuchs, Charles
    Chanock, Stephen J.
    Stolzenberg-Solomon, Rachael S.
    Amundadottir, Laufey T.
    Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 9, p. 994-+Article in journal (Refereed)
    Abstract [en]

    We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

  • 296. Woltmann, Andrea
    et al.
    Chen, Bowang
    Lascorz, Jesus
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Eyfjord, Jorunn E.
    Hamann, Ute
    Manjer, Jonas
    Enquist-Olsson, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herms, Stefan
    Hoffmann, Per
    Hemminki, Kari
    Lenner, Per
    Forsti, Asta
    Systematic Pathway Enrichment Analysis of a Genome-Wide Association Study on Breast Cancer Survival Reveals an Influence of Genes Involved in Cell Adhesion and Calcium Signaling on the Patients' Clinical Outcome2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e98229-Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWASs) may help to understand the effects of genetic polymorphisms on breast cancer (BC) progression and survival. However, they give only a focused view, which cannot capture the tremendous complexity of this disease. Therefore, we investigated data from a previously conducted GWAS on BC survival for enriched pathways by different enrichment analysis tools using the two main annotation databases Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The goal was to identify the functional categories (GO terms and KEGG pathways) that are consistently overrepresented in a statistically significant way in the list of genes generated from the single nucleotide polymorphism (SNP) data. The SNPs with allelic p-value cut-offs 0.005 and 0.01 were annotated to the genes by excluding or including a 20 kb up-and down-stream sequence of the genes and analyzed by six different tools. We identified eleven consistently enriched categories, the most significant ones relating to cell adhesion and calcium ion binding. Moreover, we investigated the similarity between our GWAS and the enrichment analyses of twelve published gene expression signatures for breast cancer prognosis. Five of them were commonly used and commercially available, five were based on different aspects of metastasis formation and two were developed from meta-analyses of published prognostic signatures. This comparison revealed similarities between our GWAS data and the general and the specific brain metastasis gene signatures as well as the Oncotype DX signature. As metastasis formation is a strong indicator of a patient's prognosis, this result reflects the survival aspect of the conducted GWAS and supports cell adhesion and calcium signaling as important pathways in cancer progression.

  • 297. Wood, Andrew R
    et al.
    Esko, Tonu
    Yang, Jian
    Vedantam, Sailaja
    Pers, Tune H
    Gustafsson, Stefan
    Chu, Audrey Y
    Estrada, Karol
    Luan, Jian'an
    Kutalik, Zoltán
    Amin, Najaf
    Buchkovich, Martin L
    Croteau-Chonka, Damien C
    Day, Felix R
    Duan, Yanan
    Fall, Tove
    Fehrmann, Rudolf
    Ferreira, Teresa
    Jackson, Anne U
    Karjalainen, Juha
    Lo, Ken Sin
    Locke, Adam E
    Mägi, Reedik
    Mihailov, Evelin
    Porcu, Eleonora
    Randall, Joshua C
    Scherag, André
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Winkler, Thomas W
    Workalemahu, Tsegaselassie
    Zhao, Jing Hua
    Absher, Devin
    Albrecht, Eva
    Anderson, Denise
    Baron, Jeffrey
    Beekman, Marian
    Demirkan, Ayse
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Fraser, Ross M
    Goel, Anuj
    Gong, Jian
    Justice, Anne E
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Lui, Julian C
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Nalls, Michael A
    Nyholt, Dale R
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Prokopenko, Inga
    Ried, Janina S
    Ripke, Stephan
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Stancáková, Alena
    Strawbridge, Rona J
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Afzal, Uzma
    Arnlöv, Johan
    Arscott, Gillian M
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Blüher, Matthias
    Bolton, Jennifer L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Buckley, Brendan M
    Buyske, Steven
    Caspersen, Ida H
    Chines, Peter S
    Clarke, Robert
    Claudi-Boehm, Simone
    Cooper, Matthew
    Daw, E Warwick
    De Jong, Pim A
    Deelen, Joris
    Delgado, Graciela
    Denny, Josh C
    Dhonukshe-Rutten, Rosalie
    Dimitriou, Maria
    Doney, Alex S F
    Dörr, Marcus
    Eklund, Niina
    Eury, Elodie
    Folkersen, Lasse
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Go, Alan S
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    de Groot, Lisette C P G M
    Groves, Christopher J
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hannemann, Anke
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hemani, Gibran
    Henders, Anjali K
    Hillege, Hans L
    Hlatky, Mark A
    Hoffmann, Wolfgang
    Hoffmann, Per
    Holmen, Oddgeir
    Houwing-Duistermaat, Jeanine J
    Illig, Thomas
    Isaacs, Aaron
    James, Alan L
    Jeff, Janina
    Johansen, Berit
    Johansson, Asa
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Junttila, Juhani
    Kho, Abel N
    Kinnunen, Leena
    Klopp, Norman
    Kocher, Thomas
    Kratzer, Wolfgang
    Lichtner, Peter
    Lind, Lars
    Lindström, Jaana
    Lobbens, Stéphane
    Lorentzon, Mattias
    Lu, Yingchang
    Lyssenko, Valeriya
    Magnusson, Patrik K E
    Mahajan, Anubha
    Maillard, Marc
    McArdle, Wendy L
    McKenzie, Colin A
    McLachlan, Stela
    McLaren, Paul J
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Narisu, Narisu
    Nauck, Matthias
    Nolte, Ilja M
    Nöthen, Markus M
    Oozageer, Laticia
    Pilz, Stefan
    Rayner, Nigel W
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Robertson, Neil R
    Rose, Lynda M
    Roussel, Ronan
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Schunkert, Heribert
    Scott, Robert A
    Sehmi, Joban
    Seufferlein, Thomas
    Shi, Jianxin
    Silventoinen, Karri
    Smit, Johannes H
    Smith, Albert Vernon
    Smolonska, Joanna
    Stanton, Alice V
    Stirrups, Kathleen
    Stott, David J
    Stringham, Heather M
    Sundström, Johan
    Swertz, Morris A
    Syvänen, Ann-Christine
    Tayo, Bamidele O
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    van Dijk, Suzanne
    van Schoor, Natasja M
    van der Velde, Nathalie
    van Heemst, Diana
    van Oort, Floor V A
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Waldenberger, Melanie
    Wennauer, Roman
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Biffar, Reiner
    Blangero, John
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bovet, Pascal
    Brambilla, Paolo
    Brown, Morris J
    Campbell, Harry
    Caulfield, Mark J
    Chakravarti, Aravinda
    Collins, Rory
    Collins, Francis S
    Crawford, Dana C
    Cupples, L Adrienne
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Golay, Alain
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Haas, David W
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Heath, Andrew C
    Hengstenberg, Christian
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Hovingh, G Kees
    Humphries, Steve E
    Hunt, Steven C
    Hypponen, Elina
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jousilahti, Pekka
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Kayser, Manfred
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Kooner, Jaspal S
    Kooperberg, Charles
    Koskinen, Seppo
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lupoli, Sara
    Madden, Pamela A F
    Männistö, Satu
    Manunta, Paolo
    Marette, André
    Matise, Tara C
    McKnight, Barbara
    Meitinger, Thomas
    Moll, Frans L
    Montgomery, Grant W
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Ouwehand, Willem H
    Pasterkamp, Gerard
    Peters, Annette
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ritchie, Marylyn
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schwarz, Peter E H
    Sebert, Sylvain
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P
    Tardif, Jean-Claude
    Tönjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    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 Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hayes, M Geoffrey
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Jukema, J Wouter
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Powell, Joseph E
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Reinmaa, Eva
    Ridker, Paul M
    Rivadeneira, Fernando
    Rotter, Jerome I
    Saaristo, Timo E
    Saleheen, Danish
    Schlessinger, David
    Slagboom, P Eline
    Snieder, Harold
    Spector, Tim D
    Strauch, Konstantin
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van der Harst, Pim
    Völzke, Henry
    Walker, Mark
    Wareham, Nicholas J
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Deloukas, Panos
    Heid, Iris M
    Lindgren, Cecilia M
    Mohlke, Karen L
    Speliotes, Elizabeth K
    Thorsteinsdottir, Unnur
    Barroso, Inês
    Fox, Caroline S
    North, Kari E
    Strachan, David P
    Beckmann, Jacques S
    Berndt, Sonja I
    Boehnke, Michael
    Borecki, Ingrid B
    McCarthy, Mark I
    Metspalu, Andres
    Stefansson, Kari
    Uitterlinden, André G
    van Duijn, Cornelia M
    Franke, Lude
    Willer, Cristen J
    Price, Alkes L
    Lettre, Guillaume
    Loos, Ruth J F
    Weedon, Michael N
    Ingelsson, Erik
    O'Connell, Jeffrey R
    Abecasis, Goncalo R
    Chasman, Daniel I
    Goddard, Michael E
    Visscher, Peter M
    Hirschhorn, Joel N
    Frayling, Timothy M
    Defining the role of common variation in the genomic and biological architecture of adult human height2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 11, p. 1173-1186Article in journal (Refereed)
    Abstract [en]

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

  • 298.
    Wu, Cuiyan
    et al.
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Liu, Huan
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Zhang, Feng'e
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Shao, Wanzhen
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Yang, Lei
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Ning, Yujie
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Wang, Sen
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Zhao, Guanghui
    Department of Knee Joint, Xi'an Hong Hui Hospital, Xi'an, P.R. China.
    Lee, Byeong Jae
    Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, Korea.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Guo, Xiong
    Long noncoding RNA expression profile reveals lncRNAs signature associated with extracellular matrix degradation in kashin-beck disease2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17553Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is a deformative, endemic osteochondropathy involving degeneration and necrosis of growth plates and articular cartilage. The pathogenesis of KBD is related to gene expression and regulation mechanisms, but long noncoding RNAs (lncRNAs) in KBD have not been investigated. In this study, we identified 316 up-regulated and 631 down-regulated lncRNAs (≥ 2-fold change) in KBD chondrocytes using microarray analysis, of which more than three-quarters were intergenic lncRNAs and antisense lncRNAs. We also identified 232 up-regulated and 427 down-regulated mRNAs (≥ 2-fold change). A lncRNA-mRNA correlation analysis combined 343 lncRNAs and 292 mRNAs to form 509 coding-noncoding gene co-expression networks (CNC networks). Eleven lncRNAs were predicted to have cis-regulated target genes, including NAV2 (neuron navigator 2), TOX (thymocyte selection-associated high mobility group box), LAMA4 (laminin, alpha 4), and DEPTOR (DEP domain containing mTOR-interacting protein). The differentially expressed mRNAs in KBD significantly contribute to biological events associated with the extracellular matrix. Meanwhile, 34 mRNAs and 55 co-expressed lncRNAs constituted a network that influences the extracellular matrix. In the network, FBLN1 and LAMA 4 were the core genes with the highest significance. These novel findings indicate that lncRNAs may play a role in extracellular matrix destruction in KBD.

  • 299. Yang, Lei
    et al.
    Zhao, Guang-Hui
    Liu, Huan
    Wang, Xi
    Guo, Xiong
    Lammi, Mikko J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi’an, People’s Republic of China.
    Field synopsis and meta-analyses of genetic epidemiological evidence for Kashin-Beck disease, an endemic osteoarthropathy in China2016In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 291, no 5, p. 1823-1833, article id 27256326Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is a chronic degenerative osteoarthropathy with unclear etiology. To provide current evidence supporting a genetic predisposition for KBD, we conducted a systematic review and meta-analysis of published literature on the genetic epidemiology of KBD. The PubMed, China National Knowledge Infrastructure and Wan Fang Data were searched up to August 2015 for articles published in English and Chinese. Genome-wide and exome sequencing, linkage, and case-control association studies for any genetic variants associated with KBD were included. Meta-analysis was performed for all single nucleotide polymorphisms (SNPs) that were evaluated in two or more studies. The effect size was summarized as odds ratios (ORs) with 95 % confidence intervals (CIs) by fixed and random effects models. A total of 24 articles were systematically reviewed. Eleven short tandem repeats on chromosomes 2, 11 and 12, 34 SNPs in 12 genes, as well as copy number variant 452 were identified as KBD susceptibility factors in individual studies. The meta-analysis of the GPX1 rs1050450, DIO2 rs225014, TrxR2 rs5748469 and HLA-DRB1 rs7745040 failed to reveal any associations with KBD. However, the meta-analysis of HLA-DRB1 rs9275295 allele A was associated with KBD (OR = 1.737, 95 % CI: 1.002-3.012). In addition, seven haplotypes in GPX1, GPX4, HLA-DRB1 and GDF5 genes also showed significant associations with KBD. In conclusions, our study could identify a number of genetic markers associated with KBD. However, the evidence does not currently support a strong association between the specific variants and KBD because of the limited number of studies, and in the future, more rigorous studies are needed to confirm KBD's links with these variants.

  • 300. Yoshida, Kazumasa
    et al.
    Bacal, Julien
    Desmarais, Damien
    Padioleau, Ismaël
    Tsaponina, Olga
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pantesco, Véronique
    Dubois, Emeric
    Parrinello, Hugues
    Skrzypczak, Magdalena
    Ginalski, Krzysztof
    Lengronne, Armelle
    Pasero, Philippe
    The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast2014In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 54, no 4, p. 691-697Article in journal (Refereed)
    Abstract [en]

    In S. cerevisiae, replication timing is controlled by epigenetic mechanisms restricting the accessibility of origins to limiting initiation factors. About 30% of these origins are located within repetitive DNA sequences such as the ribosomal DNA (rDNA) array, but their regulation is poorly understood. Here, we have investigated how histone deacetylases (HDACs) control the replication program in budding yeast. This analysis revealed that two HDACs, Rpd3 and Sir2, control replication timing in an opposite manner. Whereas Rpd3 delays initiation at late origins, Sir2 is required for the timely activation of early origins. Moreover, Sir2 represses initiation at rDNA origins, whereas Rpd3 counteracts this effect. Remarkably, deletion of SIR2 restored normal replication in rpd3Δ cells by reactivating rDNA origins. Together, these data indicate that HDACs control the replication timing program in budding yeast by modulating the ability of repeated origins to compete with single-copy origins for limiting initiation factors.

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