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  • 151. Lindstrom, Sara
    et al.
    Schumacher, Fredrick
    Siddiq, Afshan
    Travis, Ruth C.
    Campa, Daniele
    Berndt, Sonja I.
    Diver, W. Ryan
    Severi, Gianluca
    Allen, Naomi
    Andriole, Gerald
    Bueno-de-Mesquita, Bas
    Chanock, Stephen J.
    Crawford, David
    Gaziano, J. Michael
    Giles, Graham G.
    Giovannucci, Edward
    Guo, Carolyn
    Haiman, Christopher A.
    Hayes, Richard B.
    Halkjaer, Jytte
    Hunter, David J.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer, Lyon, France .
    Kaaks, Rudolf
    Kolonel, Laurence N.
    Navarro, Carmen
    Riboli, Elio
    Sacerdote, Carlotta
    Stampfer, Meir
    Stram, Daniel O.
    Thun, Michael J.
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Weinstein, Stephanie J.
    Yeager, Meredith
    Henderson, Brian
    Ma, Jing
    Le Marchand, Loic
    Albanes, Demetrius
    Kraft, Peter
    Characterizing Associations and SNP-Environment Interactions for GWAS-Identified Prostate Cancer Risk Markers-Results from BPC32011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, article id e17142Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10(-28)). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.

  • 152. Liu, Dajiang J.
    et al.
    Peloso, Gina M.
    Yu, Haojie
    Butterworth, Adam S.
    Wang, Xiao
    Mahajan, Anubha
    Saleheen, Danish
    Emdin, Connor
    Alam, Dewan
    Alves, Alexessander Couto
    Amouyel, Philippe
    Di Angelantonio, Emanuele
    Arveiler, Dominique
    Assimes, Themistocles L.
    Auer, Paul L.
    Baber, Usman
    Ballantyne, Christie M.
    Bang, Lia E.
    Benn, Marianne
    Bis, Joshua C.
    Boehnke, Michael
    Boerwinkle, Eric
    Bork-Jensen, Jette
    Bottinger, Erwin P.
    Brandslund, Ivan
    Brown, Morris
    Busonero, Fabio
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Chen, Y. Eugene
    Chen, Yii-Der Ida
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audrey Y.
    Connell, John M.
    Cucca, Francesco
    Cupples, L. Adrienne
    Damrauer, Scott M.
    Davies, Gail
    Deary, Ian J.
    Dedoussis, George
    Denny, Joshua C.
    Dominiczak, Anna
    Dube, Marie-Pierre
    Ebeling, Tapani
    Eiriksdottir, Gudny
    Esko, Tonu
    Farmaki, Aliki-Eleni
    Feitosa, Mary F.
    Ferrario, Marco
    Ferrieres, Jean
    Ford, Ian
    Fornage, Myriam
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
    Frayling, Timothy M.
    Frikke-Schmidt, Ruth
    Fritsche, Lars G.
    Frossard, Philippe
    Fuster, Valentin
    Ganesh, Santhi K.
    Gao, Wei
    Garcia, Melissa E.
    Gieger, Christian
    Giulianini, Franco
    Goodarzi, Mark O.
    Grallert, Harald
    Grarup, Niels
    Groop, Leif
    Grove, Megan L.
    Gudnason, Vilmundur
    Hansen, Torben
    Harris, Tamara B.
    Hayward, Caroline
    Hirschhorn, Joel N.
    Holmen, Oddgeir L.
    Huffman, Jennifer
    Huo, Yong
    Hveem, Kristian
    Jabeen, Sehrish
    Jackson, Anne U.
    Jakobsdottir, Johanna
    Jarvelin, Marjo-Riitta
    Jensen, Gorm B.
    Jorgensen, Marit E.
    Jukema, J. Wouter
    Justesen, Johanne M.
    Kamstrup, Pia R.
    Kanoni, Stavroula
    Karpe, Fredrik
    Kee, Frank
    Khera, Amit V.
    Klarin, Derek
    Koistinen, Heikki A.
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laakso, Markku
    Lakka, Timo
    Langenberg, Claudia
    Langsted, Anne
    Launer, Lenore J.
    Lauritzen, Torsten
    Liewald, David C. M.
    Lin, Li An
    Linneberg, Allan
    Loos, Ruth J. F.
    Lu, Yingchang
    Lu, Xiangfeng
    Magi, Reedik
    Malarstig, Anders
    Manichaikul, Ani
    Manning, Alisa K.
    Mantyselka, Pekka
    Marouli, Eirini
    Masca, Nicholas G. D.
    Maschio, Andrea
    Meigs, James B.
    Melander, Olle
    Metspalu, Andres
    Morris, Andrew P.
    Morrison, Alanna C.
    Mulas, Antonella
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Neville, Matt J.
    Nielsen, Jonas B.
    Nielsen, Sune F.
    Nordestgaard, Borge G.
    Ordovas, Jose M.
    Mehran, Roxana
    O'Donnell, Christoper J.
    Orho-Melander, Marju
    Molony, Cliona M.
    Muntendam, Pieter
    Padmanabhan, Sandosh
    Palmer, Colin N. A.
    Pasko, Dorota
    Patel, Aniruddh P.
    Pedersen, Oluf
    Perola, Markus
    Peters, Annette
    Pisinger, Charlotta
    Pistis, Giorgio
    Polasek, Ozren
    Poulter, Neil
    Psaty, Bruce M.
    Rader, Daniel J.
    Rasheed, Asif
    Rauramaa, Rainer
    Reilly, Dermot F.
    Reiner, Alex P.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rich, Stephen S.
    Ridker, Paul M.
    Rioux, John D.
    Robertson, Neil R.
    Roden, Dan M.
    Rotter, Jerome I.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Sanna, Serena
    Sattar, Naveed
    Schmidt, Ellen M.
    Scott, Robert A.
    Sever, Peter
    Sevilla, Raquel S.
    Shaffer, Christian M.
    Sim, Xueling
    Sivapalaratnam, Suthesh
    Small, Kerrin S.
    Smith, Albert V.
    Smith, Blair H.
    Somayajula, Sangeetha
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Starr, John M.
    Stirrups, Kathleen E.
    Stitziel, Nathan
    Strauch, Konstantin
    Stringham, Heather M.
    Surendran, Praveen
    Tada, Hayato
    Tall, Alan R.
    Tang, Hua
    Tardif, Jean-Claude
    Taylor, Kent D.
    Trompet, Stella
    Tsao, Philip S.
    Tuomilehto, Jaakko
    Tybjaerg-Hansen, Anne
    van Zuydam, Natalie R.
    Varbo, Anette
    Varga, Tibor V.
    Virtamo, Jarmo
    Waldenberger, Melanie
    Wang, Nan
    Wareham, Nick J.
    Warren, Helen R.
    Weeke, Peter E.
    Weinstock, Joshua
    Wessel, Jennifer
    Wilson, James G.
    Wilson, Peter W. F.
    Xu, Ming
    Yaghootkar, Hanieh
    Young, Robin
    Zeggini, Eleftheria
    Zhang, He
    Zheng, Neil S.
    Zhang, Weihua
    Zhang, Yan
    Zhou, Wei
    Zhou, Yanhua
    Zoledziewska, Magdalena
    Howson, Joanna M. M.
    Danesh, John
    McCarthy, Mark I.
    Cowan, Chad A.
    Abecasis, Goncalo
    Deloukas, Panos
    Musunuru, Kiran
    Willer, Cristen J.
    Kathiresan, Sekar
    Exome-wide association study of plasma lipids in > 300,000 individuals2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 12, p. 1758-1766Article in journal (Refereed)
    Abstract [en]

    We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

  • 153. Lo, Min-Tzu
    et al.
    Hinds, David A.
    Tung, Joyce Y.
    Franz, Carol
    Fan, Chun-Chieh
    Wang, Yunpeng
    Smeland, Olav B.
    Schork, Andrew
    Holland, Dominic
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, University of California, San Diego, La Jolla, California, USA.
    Sanyal, Nilotpal
    Escott-Price, Valentina
    Smith, Daniel J.
    O'Donovan, Michael
    Stefansson, Hreinn
    Bjornsdottir, Gyda
    Thorgeirsson, Thorgeir E.
    Stefansson, Kari
    McEvoy, Linda K.
    Dale, Anders M.
    Andreassen, Ole A.
    Chen, Chi-Hua
    Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 1, p. 152-156Article in journal (Refereed)
    Abstract [en]

    Personality is influenced by genetic and environmental factors(1) and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci(2,3), significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit- hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).

  • 154. Lo, Min-Tzu
    et al.
    Wang, Yunpeng
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA 92037, USA.
    Sanyal, Nilotpal
    Fan, Chun-Chieh
    Smeland, Olav B.
    Schork, Andrew
    Holland, Dominic
    Hinds, David A.
    Tung, Joyce Y.
    Andreassen, Ole A.
    Dale, Anders M.
    Chen, Chi-Hua
    Modeling prior information of common genetic variants improves gene discovery for neuroticism2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 22, p. 4530-4539Article in journal (Refereed)
    Abstract [en]

    Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective.

  • 155. Lokk, Kaie
    et al.
    Modhukur, Vijayachitra
    Rajashekar, Balaji
    Märtens, Kaspar
    Mägi, Reedik
    Kolde, Raivo
    Koltšina, Marina
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Vilo, Jaak
    Salumets, Andres
    Tõnisson, Neeme
    DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 4, p. r54-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DNA epigenetic modifications, such as methylation, are important regulators of tissue differentiation, contributing to processes of both development and cancer. Profiling the tissue-specific DNA methylome patterns will provide novel insights into normal and pathogenic mechanisms, as well as help in future epigenetic therapies. In this study, 17 somatic tissues from four autopsied humans were subjected to functional genome analysis using the Illumina Infinium HumanMethylation450 BeadChip, covering 486 428 CpG sites. RESULTS: Only 2% of the CpGs analyzed are hypermethylated in all 17 tissue specimens; these permanently methylated CpG sites are located predominantly in gene-body regions. In contrast, 15% of the CpGs are hypomethylated in all specimens and are primarily located in regions proximal to transcription start sites. A vast number of tissue-specific differentially methylated regions are identified and considered likely mediators of tissue-specific gene regulatory mechanisms since the hypomethylated regions are closely related to known functions of the corresponding tissue. Finally, a clear inverse correlation is observed between promoter methylation within CpG islands and gene expression data obtained from publicly available databases. CONCLUSIONS: This genome-wide methylation profiling study identified tissue-specific differentially methylated regions in 17 human somatic tissues. Many of the genes corresponding to these differentially methylated regions contribute to tissue-specific functions. Future studies may use these data as a reference to identify markers of perturbed differentiation and disease-related pathogenic mechanisms.

  • 156. Lombardi, Maria Paola
    et al.
    Bulk, Saskia
    Celli, Jacopo
    Lampe, Anne
    Gabbett, Michael T
    Ousager, Lillian Bomme
    van der Smagt, Jasper J
    Soller, Maria
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mannens, Marcel A M M
    Smigiel, Robert
    Hennekam, Raoul C
    Mutation update for the PORCN gene2011In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 32, no 7, p. 723-728Article in journal (Refereed)
    Abstract [en]

    Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients.

  • 157. Lund Laursen, Anne Cathrine
    et al.
    Sandahl, Julie Damgaard
    Kjeldsen, Eigil
    Abrahamsson, Jonas
    Asdahl, Peter
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jónsson, Ólafur G
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Forestier, Erik
    Department of Medical Biosciences, Clinical Genetics, Umeå University Hospital, Umeå, Sweden.
    Hasle, Henrik
    Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study2016In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, no 9, p. 719-726Article in journal (Refereed)
    Abstract [en]

    Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone.

  • 158. Lunetta, Kathryn L.
    et al.
    Day, Felix R.
    Sulem, Patrick
    Ruth, Katherine S.
    Tung, Joyce Y.
    Hinds, David A.
    Esko, Tonu
    Elks, Cathy E.
    Altmaier, Elisabeth
    He, Chunyan
    Huffman, Jennifer E.
    Mihailov, Evelin
    Porcu, Eleonora
    Robino, Antonietta
    Rose, Lynda M.
    Schick, Ursula M.
    Stolk, Lisette
    Teumer, Alexander
    Thompson, Deborah J.
    Traglia, Michela
    Wang, Carol A.
    Yerges-Armstrong, Laura M.
    Antoniou, Antonis C.
    Barbieri, Caterina
    Coviello, Andrea D.
    Cucca, Francesco
    Demerath, Ellen W.
    Dunning, Alison M.
    Gandin, Ilaria
    Grove, Megan L.
    Gudbjartsson, Daniel F.
    Hocking, Lynne J.
    Hofman, Albert
    Huang, Jinyan
    Jackson, Rebecca D.
    Karasik, David
    Kriebel, Jennifer
    Lange, Ethan M.
    Lange, Leslie A.
    Langenberg, Claudia
    Li, Xin
    Luan, Jian'an
    Maegi, Reedik
    Morrison, Alanna C.
    Padmanabhan, Sandosh
    Pirie, Ailith
    Polasek, Ozren
    Porteous, David
    Reiner, Alex P.
    Rivadeneira, Fernando
    Rudan, Igor
    Sala, Cinzia F.
    Schlessinger, David
    Scott, Robert A.
    Stoeckl, Doris
    Visser, Jenny A.
    Voelker, Uwe
    Vozzi, Diego
    Wilson, James G.
    Zygmunt, Marek
    Boerwinkle, Eric
    Buring, Julie E.
    Crisponi, Laura
    Easton, Douglas F.
    Hayward, Caroline
    Hu, Frank B.
    Liu, Simin
    Metspalu, Andres
    Pennell, Craig E.
    Ridker, Paul M.
    Strauch, Konstantin
    Streeten, Elizabeth A.
    Toniolo, Daniela
    Uitterlinden, Andre G.
    Ulivi, Sheila
    Voelzke, Henry
    Wareham, Nicholas J.
    Wellons, Melissa
    Franceschini, Nora
    Chasman, Daniel I.
    Thorsteinsdottir, Unnur
    Murray, Anna
    Stefansson, Kari
    Murabito, Joanne M.
    Ong, Ken K.
    Perry, John R. B.
    Forouhi, Nita G.
    Kerrison, Nicola D.
    Sharp, Stephen J.
    Sims, Matt
    Barroso, Ines
    Deloukas, Panos
    McCarthy, Mark I.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Boeing, Heiner
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gonzalez, Carlos
    Grioni, Sara
    Kaaks, Rudolf
    Key, Timothy J.
    Navarro, Carmen
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Riboli, Elio
    Smith, Blair H.
    Campbell, Archie
    Deary, Ian J.
    McIntosh, Andrew M.
    Rare coding variants and X-linked loci associated with age at menarche2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7756Article in journal (Refereed)
    Abstract [en]

    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

  • 159. Machiela, Mitchell J
    et al.
    Zhou, Weiyin
    Karlins, Eric
    Sampson, Joshua N
    Freedman, Neal D
    Yang, Qi
    Hicks, Belynda
    Dagnall, Casey
    Hautman, Christopher
    Jacobs, Kevin B
    Abnet, Christian C
    Aldrich, Melinda C
    Amos, Christopher
    Amundadottir, Laufey T
    Arslan, Alan A
    Beane-Freeman, Laura E
    Berndt, Sonja I
    Black, Amanda
    Blot, William J
    Bock, Cathryn H
    Bracci, Paige M
    Brinton, Louise A
    Bueno-de-Mesquita, H Bas
    Burdett, Laurie
    Buring, Julie E
    Butler, Mary A
    Canzian, Federico
    Carreón, Tania
    Chaffee, Kari G
    Chang, I-Shou
    Chatterjee, Nilanjan
    Chen, Chu
    Chen, Constance
    Chen, Kexin
    Chung, Charles C
    Cook, Linda S
    Crous Bou, Marta
    Cullen, Michael
    Davis, Faith G
    De Vivo, Immaculata
    Ding, Ti
    Doherty, Jennifer
    Duell, Eric J
    Epstein, Caroline G
    Fan, Jin-Hu
    Figueroa, Jonine D
    Fraumeni, Joseph F
    Friedenreich, Christine M
    Fuchs, Charles S
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Gaudet, Mia M
    Gaziano, J Michael
    Giles, Graham G
    Gillanders, Elizabeth M
    Giovannucci, Edward L
    Goldin, Lynn
    Goldstein, Alisa M
    Haiman, Christopher A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Harris, Curtis C
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holly, Elizabeth A
    Hong, Yun-Chul
    Hoover, Robert N
    Hsiung, Chao A
    Hu, Nan
    Hu, Wei
    Hunter, David J
    Hutchinson, Amy
    Jenab, Mazda
    Johansen, Christoffer
    Khaw, Kay-Tee
    Kim, Hee Nam
    Kim, Yeul Hong
    Kim, Young Tae
    Klein, Alison P
    Klein, Robert
    Koh, Woon-Puay
    Kolonel, Laurence N
    Kooperberg, Charles
    Kraft, Peter
    Krogh, Vittorio
    Kurtz, Robert C
    LaCroix, Andrea
    Lan, Qing
    Landi, Maria Teresa
    Marchand, Loic Le
    Li, Donghui
    Liang, Xiaolin
    Liao, Linda M
    Lin, Dongxin
    Liu, Jianjun
    Lissowska, Jolanta
    Lu, Lingeng
    Magliocco, Anthony M
    Malats, Nuria
    Matsuo, Keitaro
    McNeill, Lorna H
    McWilliams, Robert R
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Mirabello, Lisa
    Moore, Lee
    Olson, Sara H
    Orlow, Irene
    Park, Jae Yong
    Patiño-Garcia, Ana
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M
    Pooler, Loreall
    Prescott, Jennifer
    Prokunina-Olsson, Ludmila
    Purdue, Mark P
    Qiao, You-Lin
    Rajaraman, Preetha
    Real, Francisco X
    Riboli, Elio
    Risch, Harvey A
    Rodriguez-Santiago, Benjamin
    Ruder, Avima M
    Savage, Sharon A
    Schumacher, Fredrick
    Schwartz, Ann G
    Schwartz, Kendra L
    Seow, Adeline
    Wendy Setiawan, Veronica
    Severi, Gianluca
    Shen, Hongbing
    Sheng, Xin
    Shin, Min-Ho
    Shu, Xiao-Ou
    Silverman, Debra T
    Spitz, Margaret R
    Stevens, Victoria L
    Stolzenberg-Solomon, Rachael
    Stram, Daniel
    Tang, Ze-Zhong
    Taylor, Philip R
    Teras, Lauren R
    Tobias, Geoffrey S
    Van Den Berg, David
    Visvanathan, Kala
    Wacholder, Sholom
    Wang, Jiu-Cun
    Wang, Zhaoming
    Wentzensen, Nicolas
    Wheeler, William
    White, Emily
    Wiencke, John K
    Wolpin, Brian M
    Wong, Maria Pik
    Wu, Chen
    Wu, Tangchun
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S
    Xia, Lucy
    Yang, Hannah P
    Yang, Pan-Chyr
    Yu, Kai
    Zanetti, Krista A
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Zhou, Baosen
    Ziegler, Regina G
    Perez-Jurado, Luis A
    Caporaso, Neil E
    Rothman, Nathaniel
    Tucker, Margaret
    Dean, Michael C
    Yeager, Meredith
    Chanock, Stephen J
    Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11843Article in journal (Refereed)
    Abstract [en]

    To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.

  • 160. Machiela, Mitchell J.
    et al.
    Zhou, Weiyin
    Sampson, Joshua N.
    Dean, Michael C.
    Jacobs, Kevin B.
    Black, Amanda
    Brinton, Louise A.
    Chang, I-Shou
    Chen, Chu
    Chen, Constance
    Chen, Kexin
    Cook, Linda S.
    Bou, Marta Crous
    De Vivo, Immaculata
    Doherty, Jennifer
    Friedenreich, Christine M.
    Gaudet, Mia M.
    Haiman, Christopher A.
    Hankinson, Susan E.
    Hartge, Patricia
    Henderson, Brian E.
    Hong, Yun-Chul
    Hosgood, H. Dean, III
    Hsiung, Chao A.
    Hu, Wei
    Hunter, David J.
    Jessop, Lea
    Kim, Hee Nam
    Kim, Yeul Hong
    Kim, Young Tae
    Klein, Robert
    Kraft, Peter
    Lan, Qing
    Lin, Dongxin
    Liu, Jianjun
    Le Marchand, Loic
    Liang, Xiaolin
    Lissowska, Jolanta
    Lu, Lingeng
    Magliocco, Anthony M.
    Matsuo, Keitaro
    Olson, Sara H.
    Orlow, Irene
    Park, Jae Yong
    Pooler, Loreall
    Prescott, Jennifer
    Rastogi, Radhai
    Risch, Harvey A.
    Schumacher, Fredrick
    Seow, Adeline
    Setiawan, Veronica Wendy
    Shen, Hongbing
    Sheng, Xin
    Shin, Min-Ho
    Shu, Xiao-Ou
    VanDen Berg, David
    Wang, Jiu-Cun
    Wentzensen, Nicolas
    Wong, Maria Pik
    Wu, Chen
    Wu, Tangchun
    Wu, Yi-Long
    Xia, Lucy
    Yang, Hannah P.
    Yang, Pan-Chyr
    Zheng, Wei
    Zhou, Baosen
    Abnet, Christian C.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Amos, Christopher
    Amundadottir, Laufey T.
    Berndt, Sonja I.
    Blot, William J.
    Bock, Cathryn H.
    Bracci, Paige M.
    Burdett, Laurie
    Buring, Julie E.
    Butler, Mary A.
    Carreon, Tania
    Chatterjee, Nilanjan
    Chung, Charles C.
    Cook, Michael B.
    Cullen, Michael
    Davis, Faith G.
    Ding, Ti
    Duell, Eric J.
    Epstein, Caroline G.
    Fan, Jin-Hu
    Figueroa, Jonine D.
    Fraumeni, Joseph F., Jr.
    Freedman, Neal D.
    Fuchs, Charles S.
    Gao, Yu-Tang
    Gapstur, Susan M.
    Patino-Garcia, Ana
    Garcia-Closas, Montserrat
    Gaziano, J. Michael
    Giles, Graham G.
    Gillanders, Elizabeth M.
    Giovannucci, Edward L.
    Goldin, Lynn
    Goldstein, Alisa M.
    Greene, Mark H.
    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.
    Harris, Curtis C.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holly, Elizabeth A.
    Hoover, Robert N.
    Hu, Nan
    Hutchinson, Amy
    Jenab, Mazda
    Johansen, Christoffer
    Khaw, Kay-Tee
    Koh, Woon-Puay
    Kolonel, Laurence N.
    Kooperberg, Charles
    Krogh, Vittorio
    Kurtz, Robert C.
    LaCroix, Andrea
    Landgren, Annelie
    Landi, Maria Teresa
    Li, Donghui
    Liao, Linda M.
    Malats, Nuria
    McGlynn, Katherine A.
    McNeill, Lorna H.
    McWilliams, Robert R.
    Melin, Beatrice S.
    Mirabello, Lisa
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M.
    Prokunina-Olsson, Ludmila
    Purdue, Mark
    Qiao, You-Lin
    Rabe, Kari G.
    Rajaraman, Preetha
    Real, Francisco X.
    Riboli, Elio
    Rodriguez-Santiago, Benjamin
    Rothman, Nathaniel
    Ruder, Avima M.
    Savage, Sharon A.
    Schwartz, Ann G.
    Schwartz, Kendra L.
    Sesso, Howard D.
    Severi, Gianluca
    Silverman, Debra T.
    Spitz, Margaret R.
    Stevens, Victoria L.
    Stolzenberg-Solomon, Rachael
    Stram, Daniel
    Tang, Ze-Zhong
    Taylor, Philip R.
    Teras, Lauren R.
    Tobias, Geoffrey S.
    Viswanathan, Kala
    Wacholder, Sholom
    Wang, Zhaoming
    Weinstein, Stephanie J.
    Wheeler, William
    White, Emily
    Wiencke, John K.
    Wolpin, Brian M.
    Wu, Xifeng
    Wunder, Jay S.
    Yu, Kai
    Zanetti, Krista A.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ziegler, Regina G.
    De Andrade, Mariza
    Barnes, Kathleen C.
    Beaty, Terri H.
    Bierut, Laura J.
    Desch, Karl C.
    Doheny, Kimberly F.
    Feenstra, Bjarke
    Ginsburg, David
    Heit, John A.
    Kang, Jae H.
    Laurie, Cecilia A.
    Li, Jun Z.
    Lowe, William L.
    Marazita, Mary L.
    Melbye, Mads
    Mirel, Daniel B.
    Murray, Jeffrey C.
    Nelson, Sarah C.
    Pasquale, Louis R.
    Rice, Kenneth
    Wiggs, Janey L.
    Wise, Anastasia
    Tucker, Margaret
    Perez-Jurado, Luis A.
    Laurie, Cathy C.
    Caporaso, Neil E.
    Yeager, Meredith
    Chanock, Stephen J.
    Characterization of Large Structural Genetic Mosaicism in Human Autosomes2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 3, p. 487-497Article in journal (Refereed)
    Abstract [en]

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

  • 161. Mahajan, Anubha
    et al.
    Wessel, Jennifer
    Willems, Sara M.
    Zhao, Wei
    Robertson, Neil R.
    Chu, Audrey Y.
    Gan, Wei
    Kitajima, Hidetoshi
    Taliun, Daniel
    Rayner, N. William
    Guo, Xiuqing
    Lu, Yingchang
    Li, Man
    Jensen, Richard A.
    Hu, Yao
    Huo, Shaofeng
    Lohman, Kurt K.
    Zhang, Weihua
    Cook, James P.
    Prins, Bram Peter
    Flannick, Jason
    Grarup, Niels
    Trubetskoy, Vassily Vladimirovich
    Kravic, Jasmina
    Kim, Young Jin
    Rybin, Denis V.
    Yaghootkar, Hanieh
    Mueller-Nurasyid, Martina
    Meidtner, Karina
    Li-Gao, Ruifang
    Varga, Tibor V.
    Marten, Jonathan
    Li, Jin
    Smith, Albert Vernon
    An, Ping
    Ligthart, Symen
    Gustafsson, Stefan
    Malerba, Giovanni
    Demirkan, Ayse
    Tajes, Juan Fernandez
    Steinthorsdottir, Valgerdur
    Wuttke, Matthias
    Lecoeur, Cecile
    Preuss, Michael
    Bielak, Lawrence F.
    Graff, Marielisa
    Highland, Heather M.
    Justice, Anne E.
    Liu, Dajiang J.
    Marouli, Eirini
    Peloso, Gina Marie
    Warren, Helen R.
    Afaq, Saima
    Afzal, Shoaib
    Ahlqvist, Emma
    Almgren, Peter
    Amin, Najaf
    Bang, Lia B.
    Bertoni, Alain G.
    Bombieri, Cristina
    Bork-Jensen, Jette
    Brandslund, Ivan
    Brody, Jennifer A.
    Burtt, Noel P.
    Canouil, Mickael
    Chen, Yii-Der Ida
    Cho, Yoon Shin
    Christensen, Cramer
    Eastwood, Sophie V.
    Eckardt, Kai-Uwe
    Fischer, Krista
    Gambaro, Giovanni
    Giedraitis, Vilmantas
    Grove, Megan L.
    de Haan, Hugoline G.
    Hackinger, Sophie
    Hai, Yang
    Han, Sohee
    Tybjaerg-Hansen, Anne
    Hivert, Marie-France
    Isomaa, Bo
    Jager, Susanne
    Jorgensen, Marit E.
    Jorgensen, Torben
    Karajamaki, Annemari
    Kim, Bong-Jo
    Kim, Sung Soo
    Koistinen, Heikki A.
    Kovacs, Peter
    Kriebel, Jennifer
    Kronenberg, Florian
    Lall, Kristi
    Lange, Leslie A.
    Lee, Jung-Jin
    Lehne, Benjamin
    Li, Huaixing
    Lin, Keng-Hung
    Linneberg, Allan
    Liu, Ching-Ti
    Liu, Jun
    Loh, Marie
    Magi, Reedik
    Mamakou, Vasiliki
    McKean-Cowdin, Roberta
    Nadkarni, Girish
    Neville, Matt
    Nielsen, Sune F.
    Ntalla, Ioanna
    Peyser, Patricia A.
    Rathmann, Wolfgang
    Rice, Kenneth
    Rich, Stephen S.
    Rode, Line
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Schonherr, Sebastian
    Selvin, Elizabeth
    Small, Kerrin S.
    Stancakova, Alena
    Surendran, Praveen
    Taylor, Kent D.
    Teslovich, Tanya M.
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tin, Adrienne
    Tonjes, Anke
    Varbo, Anette
    Witte, Daniel R.
    Wood, Andrew R.
    Yajnik, Pranav
    Yao, Jie
    Yengo, Loic
    Young, Robin
    Amouyel, Philippe
    Boeing, Heiner
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Chowdhury, Rajiv
    Collins, Francis S.
    Dedoussis, George
    Dehghan, Abbas
    Deloukas, Panos
    Ferrario, Marco M.
    Ferrieres, Jean
    Florez, Jose C.
    Frossard, Philippe
    Gudnason, Vilmundur
    Harris, Tamara B.
    Heckbert, Susan R.
    Howson, Joanna M. M.
    Ingelsson, Martin
    Kathiresan, Sekar
    Kee, Frank
    Kuusisto, Johanna
    Langenberg, Claudia
    Launer, Lenore J.
    Lindgren, Cecilia M.
    Mannisto, Satu
    Meitinger, Thomas
    Melander, Olle
    Mohlke, Karen L.
    Moitry, Marie
    Morris, Andrew D.
    Murray, Alison D.
    de Mutsert, Renee
    Orho-Melander, Marju
    Owen, Katharine R.
    Perola, Markus
    Peters, Annette
    Province, Michael A.
    Rasheed, Asif
    Ridker, Paul M.
    Rivadineira, Fernando
    Rosendaal, Frits R.
    Rosengren, Anders H.
    Salomaa, Veikko
    Sheu, Wayne H. -H.
    Sladek, Rob
    Smith, Blair H.
    Strauch, Konstantin
    Uitterlinden, Andre G.
    Varma, Rohit
    Willer, Cristen J.
    Bluher, Matthias
    Butterworth, Adam S.
    Chambers, John Campbell
    Chasman, Daniel I.
    Danesh, John
    van Duijn, Cornelia
    Dupuis, Josee
    Franco, Oscar H.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Froguel, Philippe
    Grallert, Harald
    Groop, Leif
    Han, Bok-Ghee
    Hansen, Torben
    Hattersley, Andrew T.
    Hayward, Caroline
    Ingelsson, Erik
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kooner, Jaspal Singh
    Kottgen, Anna
    Kuulasmaa, Kari
    Laakso, Markku
    Lin, Xu
    Lind, Lars
    Liu, Yongmei
    Loos, Ruth J. F.
    Marchini, Jonathan
    Metspalu, Andres
    Mook-Kanamori, Dennis
    Nordestgaard, Borge G.
    Palmer, Colin N. A.
    Pankow, James S.
    Pedersen, Oluf
    Psaty, Bruce M.
    Rauramaa, Rainer
    Sattar, Naveed
    Schulze, Matthias B.
    Soranzo, Nicole
    Spector, Timothy D.
    Stefansson, Kari
    Stumvoll, Michael
    Thorsteinsdottir, Unnur
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Wareham, Nicholas J.
    Wilson, James G.
    Zeggini, Eleftheria
    Scott, Robert A.
    Barroso, Ines
    Frayling, Timothy M.
    Goodarzi, Mark O.
    Meigs, James B.
    Boehnke, Michael
    Saleheen, Danish
    Morris, Andrew P.
    Rotter, Jerome I.
    McCarthy, Mark I.
    Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 4, p. 559-571Article in journal (Refereed)
    Abstract [en]

    We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

  • 162. Majhen, Dragomira
    et al.
    Calderon, Hugo
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Alberto Fajardo, Carlos
    Rajan, Anandi
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Alemany, Ramon
    Custers, Jerome
    Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field2014In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 25, no 4, p. 301-317Article, review/survey (Refereed)
    Abstract [en]

    The field of adenovirology is undergoing rapid change in response to increasing appreciation of the potential advantages of adenoviruses as the basis for new vaccines and as vectors for gene and cancer therapy. Substantial knowledge and understanding of adenoviruses at a molecular level has made their manipulation for use as vaccines and therapeutics relatively straightforward in comparison with other viral vectors. In this review we summarize the structure and life cycle of the adenovirus and focus on the use of adenovirus-based vectors in vaccines against infectious diseases and cancers. Strategies to overcome the problem of preexisting antiadenovirus immunity, which can hamper the immunogenicity of adenovirus-based vaccines, are discussed. When armed with tumor-associated antigens, replication-deficient and oncolytic adenoviruses can efficiently activate an antitumor immune response. We present concepts on how to use adenoviruses as therapeutic cancer vaccines and consider some of the strategies used to further improve antitumor immune responses. Studies that explore the prospect of adenoviruses as vaccines against infectious diseases and cancer are underway, and here we give an overview of the latest developments.

  • 163. Malmo, Jostein
    et al.
    Sandvig, Axel
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Varum, Kjell M.
    Strand, Sabina P.
    Nanoparticle Mediated P-Glycoprotein Silencing for Improved Drug Delivery across the Blood-Brain Barrier: A siRNA-Chitosan Approach2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e54182-Article in journal (Refereed)
    Abstract [en]

    The blood-brain barrier (BBB), composed of tightly organized endothelial cells, limits the availability of drugs to therapeutic targets in the central nervous system. The barrier is maintained by membrane bound efflux pumps efficiently transporting specific xenobiotics back into the blood. The efflux pump P-glycoprotein (P-gp), expressed at high levels in brain endothelial cells, has several drug substrates. Consequently, siRNA mediated silencing of the P-gp gene is one possible strategy how to improve the delivery of drugs to the brain. Herein, we investigated the potential of siRNA-chitosan nanoparticles in silencing P-gp in a BBB model. We show that the transfection of rat brain endothelial cells mediated effective knockdown of P-gp with subsequent decrease in P-gp substrate efflux. This resulted in increased cellular delivery and efficacy of the model drug doxorubicin.

  • 164. Manning, Alisa K.
    et al.
    Hivert, Marie-France
    Scott, Robert A.
    Grimsby, Jonna L.
    Bouatia-Naji, Nabila
    Chen, Han
    Rybin, Denis
    Liu, Ching-Ti
    Bielak, Lawrence F.
    Prokopenko, Inga
    Amin, Najaf
    Barnes, Daniel
    Cadby, Gemma
    Hottenga, Jouke-Jan
    Ingelsson, Erik
    Jackson, Anne U.
    Johnson, Toby
    Kanoni, Stavroula
    Ladenvall, Claes
    Lagou, Vasiliki
    Lahti, Jari
    Lecoeur, Cecile
    Liu, Yongmei
    Martinez-Larrad, Maria Teresa
    Montasser, May E.
    Navarro, Pau
    Perry, John R. B.
    Rasmussen-Torvik, Laura J.
    Salo, Perttu
    Sattar, Naveed
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Strawbridge, Rona J.
    Tanaka, Toshiko
    van Duijn, Cornelia M.
    An, Ping
    de Andrade, Mariza
    Andrews, Jeanette S.
    Aspelund, Thor
    Atalay, Mustafa
    Aulchenko, Yurii
    Balkau, Beverley
    Bandinelli, Stefania
    Beckmann, Jacques S.
    Beilby, John P.
    Bellis, Claire
    Bergman, Richard N.
    Blangero, John
    Boban, Mladen
    Boehnke, Michael
    Boerwinkle, Eric
    Bonnycastle, Lori L.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    Boettcher, Yvonne
    Bouchard, Claude
    Brunner, Eric
    Budimir, Danijela
    Campbell, Harry
    Carlson, Olga
    Chines, Peter S.
    Clarke, Robert
    Collins, Francis S.
    Corbaton-Anchuelo, Arturo
    Couper, David
    de Faire, Ulf
    Dedoussis, George V.
    Deloukas, Panos
    Dimitriou, Maria
    Egan, Josephine M.
    Eiriksdottir, Gudny
    Erdos, Michael R.
    Eriksson, Johan G.
    Eury, Elodie
    Ferrucci, Luigi
    Ford, Ian
    Forouhi, Nita G.
    Fox, Caroline S.
    Franzosi, Maria Grazia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Frayling, Timothy M.
    Froguel, Philippe
    Galan, Pilar
    de Geus, Eco
    Gigante, Bruna
    Glazer, Nicole L.
    Goel, Anuj
    Groop, Leif
    Gudnason, Vilmundur
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hamsten, Anders
    Hansson, Ola
    Harris, Tamara B.
    Hayward, Caroline
    Heath, Simon
    Hercberg, Serge
    Hicks, Andrew A.
    Hingorani, Aroon
    Hofman, Albert
    Hui, Jennie
    Hung, Joseph
    Jarvelin, Marjo-Riitta
    Jhun, Min A.
    Johnson, Paul C. D.
    Jukema, J. Wouter
    Jula, Antti
    Kao, W. H.
    Kaprio, Jaakko
    Kardia, Sharon L. R.
    Keinanen-Kiukaanniemi, Sirkka
    Kivimaki, Mika
    Kolcic, Ivana
    Kovacs, Peter
    Kumari, Meena
    Kuusisto, Johanna
    Kyvik, Kirsten Ohm
    Laakso, Markku
    Lakka, Timo
    Lannfelt, Lars
    Lathrop, G. Mark
    Launer, Lenore J.
    Leander, Karin
    Li, Guo
    Lind, Lars
    Lindstrom, Jaana
    Lobbens, Stephane
    Loos, Ruth J. F.
    Luan, Jian'an
    Lyssenko, Valeriya
    Magi, Reedik
    Magnusson, Patrik K. E.
    Marmot, Michael
    Meneton, Pierre
    Mohlke, Karen L.
    Mooser, Vincent
    Morken, Mario A.
    Miljkovic, Iva
    Narisu, Narisu
    O'Connell, Jeff
    Ong, Ken K.
    Oostra, Ben A.
    Palmer, Lyle J.
    Palotie, Aarno
    Pankow, James S.
    Peden, John F.
    Pedersen, Nancy L.
    Pehlic, Marina
    Peltonen, Leena
    Penninx, Brenda
    Pericic, Marijana
    Perola, Markus
    Perusse, Louis
    Peyser, Patricia A.
    Polasek, Ozren
    Pramstaller, Peter P.
    Province, Michael A.
    Raikkonen, Katri
    Rauramaa, Rainer
    Rehnberg, Emil
    Rice, Ken
    Rotter, Jerome I.
    Rudan, Igor
    Ruokonen, Aimo
    Saaristo, Timo
    Sabater-Lleal, Maria
    Salomaa, Veikko
    Savage, David B.
    Saxena, Richa
    Schwarz, Peter
    Seedorf, Udo
    Sennblad, Bengt
    Serrano-Rios, Manuel
    Shuldiner, Alan R.
    Sijbrands, Eric J. G.
    Siscovick, David S.
    Smit, Johannes H.
    Small, Kerrin S.
    Smith, Nicholas L.
    Smith, Albert Vernon
    Stancakova, Alena
    Stirrups, Kathleen
    Stumvoll, Michael
    Sun, Yan V.
    Swift, Amy J.
    Toenjes, Anke
    Tuomilehto, Jaakko
    Trompet, Stella
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Vikstrom, Max
    Vitart, Veronique
    Vohl, Marie-Claude
    Voight, Benjamin F.
    Vollenweider, Peter
    Waeber, Gerard
    Waterworth, Dawn M.
    Watkins, Hugh
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wheeler, Eleanor
    Widen, Elisabeth
    Wild, Sarah H.
    Willems, Sara M.
    Willemsen, Gonneke
    Wilson, James F.
    Witteman, Jacqueline C. M.
    Wright, Alan F.
    Yaghootkar, Hanieh
    Zelenika, Diana
    Zemunik, Tatijana
    Zgaga, Lina
    Wareham, Nicholas J.
    McCarthy, Mark I.
    Barroso, Ines
    Watanabe, Richard M.
    Florez, Jose C.
    Dupuis, Josee
    Meigs, James B.
    Langenberg, Claudia
    A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 6, p. 659-669Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

  • 165.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Genetic studies of diabetes in northern Sweden2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetes mellitus represents a group of metabolic disorders caused by both environmental and genetic factors. The two most common forms of diabetes are type 2 diabetes (T2D) and type 1 diabetes (T1D). T2D is associated with obesity and the disease is caused by insulin resistance and pancreatic b-cell dysfunction. T1D is an autoimmune disease in which the insulin- producing b-cells in the pancreas are destroyed by infiltration of lymphocytes.

    The aim of this thesis was to identify genes conferring susceptibility to diabetes. This was approached using genetic methods, both linkage and association studies, within the population of northern Sweden.

    The northern Swedish population is well suited for genetic studies of familial forms of disease, since an internal expansion of the northern Swedish population, coupled with a low frequency of immigration and a high frequency of consanguineous marriages, has resulted in a relatively homogeneous gene pool. This simplified genetic background increases the probability of identifying genes contributing to disease.

    The family-based material used for the type 2 diabetes studies (papers I and II) consisted of 231 individuals from 59 families originating in northern Sweden. The type 2 diabetes case-control material (papers I and II) consisted of 872 cases and 857 matched controls, all from northern Sweden. In paper I we performed a genome-wide linkage scan, seeking T2D susceptibility loci. Linkage to the previously identified Calpain-10 region was found, however, association studies in the case-control material revealed no association to the CAPN10 gene. Using both the family-based and the case-control material, we were able to confirm the association of polymorphisms in the TCF7L2 gene to T2D in the population of northern Sweden (paper II).

    CTLA-4 is a negative regulator of T cell activity, belonging to the CD28 co-stimulatory receptor family. Numerous reports, including our own, have associated CTLA-4 variants with T1D as well as other autoimmune diseases, such as autoimmune thyroid disease (AITD). Allelic variation in the 3ÚTR of the CTLA-4 gene was associated to human T1D and this variant has also been suggested to affect the level of mRNA encoding the soluble form of the molecule (sCTLA-4). We confirmed the association of allelic variation in the 3ÚTR of the CTLA-4 gene in a T1D/AITD case-control material from northern Sweden, consisting of 104 individuals with ATID, 149 individuals with T1D and 865 matched controls. However, we were unable to identify any correlation between allelic variants in the 3ÚTR of the CTLA-4 gene and expression of sCTLA-4 (paper III).

    Based on recently published genome-wide association (GWA) scans, 33 single-nucleotide polymorphisms (SNPs) located within 16 genes were selected for an association analysis in T1D/AITD families from northern Sweden. The T1D/AITD family-based material consisted of 253 cases and 206 healthy individuals from 97 northern Swedish families. Analysis revealed association to T1D for SNPs in PTPN22, COL1A2, IL-2Ra and INS. In addition, SNPs in CTLA-4, IL-2 and C12orf30 were shown to be associated to AITD (paper IV).

    Together, these results underpin the notion that the population of northern Sweden is well suited for the detection of genes involved in complex diseases. The use of our more restricted patient material, compared to materials used in published GWA scans, enables the discovery of disease associated genes in a more cost effective manner and show that our population is capable of detecting general susceptibility genes.

  • 166.
    Mayans, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ruikka, Karin
    Department of Medicine, Sunderby Hospital, Luleå.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Sunderby Hospital, Luleå.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, p. 342-346Article in journal (Refereed)
    Abstract [en]

    A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case-control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case-control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.

  • 167.
    Mayans, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nyholm, Caroline
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ruikka, Karin
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cilio, Corrado M
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden2007In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 8, article id 3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms in and around the CTLA-4 gene have previously been associated to T1D and AITD in several populations. One such single nucleotide polymorphism (SNP), CT60, has been reported to affect the expression level ratio of the soluble (sCTLA-4) to full length CTLA-4 (flCTLA-4) isoforms. The aims of our study were to replicate the association previously published by Ueda et al. of polymorphisms in the CTLA-4 region to T1D and AITD and to determine whether the CT60 polymorphism affects the expression level ratio of sCTLA-4/flCTLA-4 in our population.

    METHODS: Three SNPs were genotyped in 253 cases (104 AITD cases and 149 T1D cases) and 865 ethnically matched controls. Blood from 23 healthy individuals was used to quantify mRNA expression of CTLA-4 isoforms in CD4+ cells using real-time PCR. Serum from 102 cases and 59 healthy individuals was used to determine the level of sCTLA-4 protein.

    RESULTS: Here we show association of the MH30, CT60 and JO31 polymorphisms to T1D and AITD in northern Sweden. We also observed a higher frequency of the CT60 disease susceptible allele in our controls compared to the British, Italian and Dutch populations, which might contribute to the high frequency of T1D in Sweden. In contrast to previously published findings, however, we were unable to find differences in the sCTLA-4/flCTLA-4 expression ratio based on the CT60 genotype in 23 healthy volunteers, also from northern Sweden. Analysis of sCTLA-4 protein levels in serum showed no correlation between sCTLA-4 protein levels and disease status or CT60 genotype.

    CONCLUSION: Association was found between T1D/AITD and all three polymorphisms investigated. However, in contrast to previous investigations, sCTLA-4 RNA and protein expression levels did not differ based on CT60 genotype. Our results do not rule out the CT60 SNP as an important polymorphism in the development of T1D or AITD, but suggest that further investigations are necessary to elucidate the effect of the CTLA-4 region on the development of T1D and AITD.

  • 168. McKay, James D.
    et al.
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Carreras-Torres, Robert
    Christiani, David C.
    Caporaso, Neil E.
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Byun, Jinyoung
    Dunning, Alison
    Pooley, Karen A.
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Timofeeva, Maria N.
    Bojesen, Stig E.
    Wu, Xifeng
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeböller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    Teare, M. Dawn
    Field, John K.
    Kiemeney, Lambertus A.
    Lazarus, Philip
    Haugen, Aage
    Lam, Stephen
    Schabath, Matthew B.
    Andrew, Angeline S.
    Shen, Hongbing
    Hong, Yun-Chul
    Yuan, Jian-Min
    Bertazzi, Pier Alberto
    Pesatori, Angela C.
    Ye, Yuanqing
    Diao, Nancy
    Su, Li
    Zhang, Ruyang
    Brhane, Yonathan
    Leighl, Natasha
    Johansen, Jakob S.
    Mellemgaard, Anders
    Saliba, Walid
    Haiman, Christopher A.
    Wilkens, Lynne R.
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    van der Heijden, Henricus F. M.
    Kim, Jin Hee
    Dai, Juncheng
    Hu, Zhibin
    Davies, Michael P. A.
    Marcus, Michael W.
    Brunnström, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Doherty, Jennifer A.
    Barnett, Matt P.
    Chen, Chu
    Goodman, Gary E.
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Brüske, Irene
    Wichmann, H-Erich
    Manz, Judith
    Muley, Thomas R.
    Risch, Angela
    Rosenberger, Albert
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Shepherd, Frances A.
    Tsao, Ming-Sound
    Arnold, Susanne M.
    Haura, Eric B.
    Bolca, Ciprian
    Holcatova, Ivana
    Janout, Vladimir
    Kontic, Milica
    Lissowska, Jolanta
    Mukeria, Anush
    Ognjanovic, Simona
    Orlowski, Tadeusz M.
    Scelo, Ghislaine
    Swiatkowska, Beata
    Zaridze, David
    Bakke, Per
    Skaug, Vidar
    Zienolddiny, Shanbeh
    Duell, Eric J.
    Butler, Lesley M.
    Koh, Woon-Puay
    Gao, Yu-Tang
    Houlston, Richard S.
    McLaughlin, John
    Stevens, Victoria L.
    Joubert, Philippe
    Lamontagne, Maxime
    Nickle, David C.
    Obeidat, Ma'en
    Timens, Wim
    Zhu, Bin
    Song, Lei
    Kachuri, Linda
    Artigas, Maria Soler
    Tobin, Martin D.
    Wain, Louise V.
    Rafnar, Thorunn
    Thorgeirsson, Thorgeir E.
    Reginsson, Gunnar W.
    Stefansson, Kari
    Hancock, Dana B.
    Bierut, Laura J.
    Spitz, Margaret R.
    Gaddis, Nathan C.
    Lutz, Sharon M.
    Gu, Fangyi
    Johnson, Eric O.
    Kamal, Ahsan
    Pikielny, Claudio
    Zhu, Dakai
    Lindström, Sara
    Jiang, Xia
    Tyndale, Rachel F.
    Chenevix-Trench, Georgia
    Beesley, Jonathan
    Bossé, Yohan
    Chanock, Stephen
    Brennan, Paul
    Landi, Maria Teresa
    Amos, Christopher I.
    Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 7, p. 1126-1132Article in journal (Refereed)
    Abstract [en]

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  • 169. McKay, James D.
    et al.
    Truong, Therese
    Gaborieau, Valerie
    Chabrier, Amelie
    Chuang, Shu-Chun
    Byrnes, Graham
    Zaridze, David
    Shangina, Oxana
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Bucur, Alexandru
    Bencko, Vladimir
    Holcatova, Ivana
    Janout, Vladimir
    Foretova, Lenka
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Benhamou, Simone
    Bouchardy, Christine
    Ahrens, Wolfgang
    Merletti, Franco
    Richiardi, Lorenzo
    Talamini, Renato
    Barzan, Luigi
    Kjaerheim, Kristina
    Macfarlane, Gary J.
    Macfarlane, Tatiana V.
    Simonato, Lorenzo
    Canova, Cristina
    Agudo, Antonio
    Castellsague, Xavier
    Lowry, Ray
    Conway, David I.
    McKinney, Patricia A.
    Healy, Claire M.
    Toner, Mary E.
    Znaor, Ariana
    Curado, Maria Paula
    Koifman, Sergio
    Menezes, Ana
    Wuensch-Filho, Victor
    Neto, Jose Eluf
    Fernandez Garrote, Leticia
    Boccia, Stefania
    Cadoni, Gabriella
    Arzani, Dario
    Olshan, Andrew F.
    Weissler, Mark C.
    Funkhouser, William K.
    Luo, Jingchun
    Lubinski, Jan
    Trubicka, Joanna
    Lener, Marcin
    Oszutowska, Dorota
    Schwartz, Stephen M.
    Chen, Chu
    Fish, Sherianne
    Doody, David R.
    Muscat, Joshua E.
    Lazarus, Philip
    Gallagher, Carla J.
    Chang, Shen-Chih
    Zhang, Zuo-Feng
    Wei, Qingyi
    Sturgis, Erich M.
    Wang, Li-E
    Franceschi, Silvia
    Herrero, Rolando
    Kelsey, Karl T.
    McClean, Michael D.
    Marsit, Carmen J.
    Nelson, Heather H.
    Romkes, Marjorie
    Buch, Shama
    Nukui, Tomoko
    Zhong, Shilong
    Lacko, Martin
    Manni, Johannes J.
    Peters, Wilbert H. M.
    Hung, Rayjean J.
    McLaughlin, John
    Vatten, Lars
    Njolstad, Inger
    Goodman, Gary E.
    Field, John K.
    Liloglou, Triantafillos
    Vineis, Paolo
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Tumino, Rosario
    Krogh, Vittorio
    Panico, Salvatore
    Gonzalez, Carlos A.
    Ramon Quiros, J.
    Martinez, Carmen
    Navarro, Carmen
    Ardanaz, Eva
    Larranaga, Nerea
    Khaw, Kay-Tee
    Key, Timothy
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H. M.
    Trichopoulou, Antonia
    Linseisen, Jakob
    Boeing, Heiner
    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.
    Overvad, Kim
    Tjonneland, Anne
    Kumle, Merethe
    Riboli, Elio
    Vaelk, Kristjan
    Voodern, Tonu
    Metspalu, Andres
    Zelenika, Diana
    Boland, Anne
    Delepine, Marc
    Foglio, Mario
    Lechner, Doris
    Blanche, Helene
    Gut, Ivo G.
    Galan, Pilar
    Heath, Simon
    Hashibe, Mia
    Hayes, Richard B.
    Boffetta, Paolo
    Lathrop, Mark
    Brennan, Paul
    A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium2011In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 3, article id e1001333Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  • 170.
    Melin, Beatrice S.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Barnholtz-Sloan, Jill S.
    Wrensch, Margaret R.
    Johansen, Christoffer
    Il'yasova, Dora
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Chen, Yanwen
    Armstrong, Georgina
    Liu, Yanhong
    Eckel-Passow, Jeanette E.
    Decker, Paul A.
    Labussiere, Marianne
    Idbaih, Ahmed
    Hoang-Xuan, Khe
    Di Stefano, Anna-Luisa
    Mokhtari, Karima
    Delattre, Jean-Yves
    Broderick, Peter
    Galan, Pilar
    Gousias, Konstantinos
    Schramm, Johannes
    Schoemaker, Minouk J.
    Fleming, Sarah J.
    Herms, Stefan
    Heilmann, Stefanie
    Noethen, Markus M.
    Wichmann, Heinz-Erich
    Schreiber, Stefan
    Swerdlow, Anthony
    Lathrop, Mark
    Simon, Matthias
    Sanson, Marc
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rajaraman, Preetha
    Chanock, Stephen
    Linet, Martha
    Wang, Zhaoming
    Yeager, Meredith
    Wiencke, John K.
    Hansen, Helen
    Mccoy, Lucie
    Rice, Terri
    Kosel, Matthew L.
    Sicotte, Hugues
    Amos, Christopher I.
    Bernstein, Jonine L.
    Davis, Faith
    Lachance, Dan
    Lau, Ching
    Merrell, Ryan T.
    Shildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Scheurer, Michael
    Shete, Sanjay
    Lai, Rose K.
    Claus, Elizabeth B.
    Olson, Sara H.
    Jenkins, Robert B.
    Houlston, Richard S.
    Bondy, Melissa L.
    Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 5, p. 789-794Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 x 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 x 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 x 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 x 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 x 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 x 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 x 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 x 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 x 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 x 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 x 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 x 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 x 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  • 171. Mendlewicz, Julien
    et al.
    Souery, Daniel
    Del-Favero, Jurgen
    Massat, Isabelle
    Lindblad, Kerstin
    Engström, Christer
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Van den Bossche, Dirk
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Schalling, Martin
    Van Broeckhoven, Christine
    Expanded RED products and loci containing CAG/CTG repeats on chromosome 17 (ERDA1) and chromosome 18 (CTG18.1) in trans-generational pairs with bipolar affective disorder2004In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 128B, no 1, p. 71-75Article in journal (Refereed)
    Abstract [en]

    The purpose of the present study was to further test if expanded CAG repeats detected by the repeat expansion detection (RED) method in bipolar affective disorder (BPAD) are correlated with ERDA1 (17q21.3) and/or CTG18.1 (18q21.1) loci expansions, and changes of phenotype severity in successive generations (anticipation). The sample was designed to analyze ERDA1 and CTG18.1 expansions in trans-generational pairs of affected individuals (parent-offspring pairs: G1 and G2). Clinical and genetic information was available on 95 two-generations pairs. We found in our sample no one patient.

  • 172.
    Mendoza-Garcia, Patricia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hugosson, Fredrik
    Fallah, Mahsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Higgins, Michael L.
    Iwasaki, Yasuno
    Pfeifer, Kathrin
    Wolfstetter, Georg
    Varshney, Gaurav
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Popichenko, Dmitry
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gergen, J. Peter
    Hens, Korneel
    Deplancke, Bart
    Palmer, Ruth H.
    The Zic family homologue Odd-paired regulates Alk expression in Drosophila2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006617Article in journal (Refereed)
    Abstract [en]

    The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression. Further characterization identifies evolutionarily conserved Opa-binding cis-regulatory motifs in one of the Alk associated enhancer elements. Employing Alk reporter lines as well as CRISPR/Cas9-mediated removal of regulatory elements in the Alk locus, we show modulation of Alk expression by Opa in the embryonic AS, epidermis and VM. In addition, we identify enhancer elements that integrate input from additional TFs, such as Binou (Bin) and Bagpipe (Bap), to regulate VM expression of Alk in a combinatorial manner. Taken together, our data show that the Opa zinc finger TF is a novel regulator of embryonic Alk expression.

  • 173.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 7, p. 649-659Article in journal (Refereed)
    Abstract [en]

    DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

  • 174.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Heart centre, Umeå.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Heart centre, Umeå.
    Cardiovascular genetics: the ultimate investigation for optimum management?2013In: International Cardiovascular Forum Journal, ISSN 2410-2636, Vol. 1, no 2, p. 57-58Article in journal (Other academic)
  • 175. Navarro-Gonzalez, Carmen
    et al.
    Moukadiri, Ismail
    Villarroya, Magda
    Lopez-Pascual, Ernesto
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eugenia Armengod, M.
    Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 7, article id e1006921Article in journal (Refereed)
    Abstract [en]

    Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu-1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell's maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype, which must be taken into consideration in exploring specific therapeutic interventions.

  • 176. Nead, Kevin T.
    et al.
    Li, Aihua
    Wehner, Mackenzie R.
    Neupane, Binod
    Gustafsson, Stefan
    Butterworth, Adam
    Engert, James C.
    Davis, A. Darlene
    Hegele, Robert A.
    Miller, Ruby
    den Hoed, Marcel
    Khaw, Kay-Tee
    Kilpelaeinen, Tuomas O.
    Wareham, Nick
    Edwards, Todd L.
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Varga, Tibor V.
    Kardia, Sharon L. R.
    Smith, Jennifer A.
    Zhao, Wei
    Faul, Jessica D.
    Weir, David
    Mi, Jie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Xi, Bo
    Quinteros, Samuel Canizales
    Cooper, Cyrus
    Sayer, Avan Aihie
    Jameson, Karen
    Grontved, Anders
    Fornage, Myriam
    Sidney, Stephen
    Hanis, Craig L.
    Highland, Heather M.
    Haering, Hans-Ulrich
    Heni, Martin
    Lasky-Su, Jessica
    Weiss, Scott T.
    Gerhard, Glenn S.
    Still, Christopher
    Melka, Melkaey M.
    Pausova, Zdenka
    Paus, Tomas
    Grant, Struan F. A.
    Hakonarson, Hakon
    Price, R. Arlen
    Wang, Kai
    Scherag, Andre
    Hebebrand, Johannes
    Hinney, Anke
    Franks, Paul W.
    Frayling, Timothy M.
    McCarthy, Mark I.
    Hirschhorn, Joel N.
    Loos, Ruth J.
    Ingelsson, Erik
    Gerstein, Hertzel C.
    Yusuf, Salim
    Beyene, Joseph
    Anand, Sonia S.
    Meyre, David
    Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3582-3594Article in journal (Refereed)
    Abstract [en]

    Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) a parts per thousand yen 40 kg/m(2)], but their contribution to common obesity (BMI a parts per thousand yen 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 x 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 x 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (beta = 0.02, 95% CI 0.00-0.03; P = 5.57 x 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

  • 177. Nelson, Christopher P.
    et al.
    Goel, Anuj
    Butterworth, Adam S.
    Kanoni, Stavroula
    Webb, Tom R.
    Marouli, Eirini
    Zeng, Lingyao
    Ntalla, Ioanna
    Lai, Florence Y.
    Hopewell, Jemma C.
    Giannakopoulou, Olga
    Jiang, Tao
    Hamby, Stephen E.
    Di Angelantonio, Emanuele
    Assimes, Themistocles L.
    Bottinger, Erwin P.
    Chambers, John C.
    Clarke, Robert
    Palmer, Colin N. A.
    Cubbon, Richard M.
    Ellinor, Patrick
    Ermel, Raili
    Evangelou, Evangelos
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
    Grace, Christopher
    Gu, Dongfeng
    Hingorani, Aroon D.
    Howson, Joanna M. M.
    Ingelsson, Erik
    Kastrati, Adnan
    Kessler, Thorsten
    Kyriakou, Theodosios
    Lehtimaki, Terho
    Lu, Xiangfeng
    Lu, Yingchang
    Maerz, Winfried
    McPherson, Ruth
    Metspalu, Andres
    Pujades-Rodriguez, Mar
    Ruusalepp, Arno
    Schadt, Eric E.
    Schmidt, Amand F.
    Sweeting, Michael J.
    Zalloua, Pierre A.
    AlGhalayini, Kamal
    Keavney, Bernard D.
    Kooner, Jaspal S.
    Loos, Ruth J. F.
    Patel, Riyaz S.
    Rutter, Martin K.
    Tomaszewski, Maciej
    Tzoulaki, Ioanna
    Zeggini, Eleftheria
    Erdmann, Jeanette
    Dedoussis, George
    Bjorkegren, Johan L. M.
    Schunkert, Heribert
    Farrall, Martin
    Danesh, John
    Samani, Nilesh J.
    Watkins, Hugh
    Deloukas, Panos
    Association analyses based on false discovery rate implicate new loci for coronary artery disease2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 9, p. 1385-1391Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 x 10(-8)) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1-4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n(cases) = 10,801) as well as a stricter definition without angina (HARD; n(cases) = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS(2,3). This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold(2), thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

  • 178. Nettleton, Jennifer A
    et al.
    Follis, Jack L
    Ngwa, Julius S
    Smith, Caren E
    Ahmad, Shafqat
    Tanaka, Toshiko
    Wojczynski, Mary K
    Voortman, Trudy
    Lemaitre, Rozenn N
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Houston, Denise K
    Perälä, Mia-Maria
    Qi, Qibin
    Sonestedt, Emily
    Manichaikul, Ani
    Kanoni, Stavroula
    Ganna, Andrea
    Mikkilä, Vera
    North, Kari E
    Siscovick, David S
    Harald, Kennet
    Mckeown, Nicola M
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rissanen, Harri
    Liu, Yongmei
    Lahti, Jari
    Hu, Frank B
    Bandinelli, Stefania
    Rukh, Gull
    Rich, Stephen
    Booij, Lisanne
    Dmitriou, Maria
    Ax, Erika
    Raitakari, Olli
    Mukamal, Kenneth
    Männistö, Satu
    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.
    Jula, Antti
    Ericson, Ulrika
    Jacobs, David R, Jr
    Van Rooij, Frank J A
    Deloukas, Panos
    Sjögren, Per
    Kähönen, Mika
    Djousse, Luc
    Perola, Markus
    Barroso, Inês
    Hofman, Albert
    Stirrups, Kathleen
    Viikari, Jorma
    Uitterlinden, André G
    Kalafati, Ioanna P
    Franco, Oscar H.
    Mozaffarian, Dariush
    Salomaa, Veikko
    Borecki, Ingrid B
    Knekt, Paul
    Kritchevsky, Stephen B
    Eriksson, Johan G
    Dedoussis, George V
    Qi, Lu
    Ferrucci, Luigi
    Orho-Melander, Marju
    Zillikens, M Carola
    Ingelsson, Erik
    Lehtimäki, Terho
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden.
    Cupples, L Adrienne
    Loos, Ruth J F
    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, Sweden; Department of Nutrition, Harvard Chan School of Public Health, Boston, MA, USA.
    Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 16, p. 4728-4738Article in journal (Refereed)
    Abstract [en]

    Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

  • 179.
    Nilsson Ardnor, Sofie
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Genetic studies of stroke in Northern Sweden2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stroke is a common disorder of later life with a complex etiology, including both environmental and genetic risk factors. The inherited predisposition is challenging to study due to the complexity of the stroke phenotype. Genetic studies in an isolated population have successfully identified a positional candidate gene for stroke, phosphodiesterase 4D (PDE4D).

    The aim of this thesis was to identify stroke susceptibility loci and positional candidate genes, taking advantage of low genetic variation in the northern Sweden population. All stroke cases were identified in a population-based stroke registry at the northern Sweden MONICA Centre. 56 families containing multiple cases of stroke and a follow up set of an additional 53 families were used for linkage studies. For association studies, 275 cases of first ever stroke together with 550 matched community controls were included. In paper I, we used a candidate region approach to investigate the PDE4D region on chromosome 5q. Linkage was obtained with a maximum allele-sharing LOD score of 2.06; P = 0.001. However, no significant association of ischemic stroke to the previously defined at-risk allele in PDE4D was observed. We next performed a genome wide linkage scan to explore new susceptibility loci for common forms of stroke (paper II). Non-parametric multipoint linkage analysis yielded allele-sharing LOD scores > 1.2 at nine locations; 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, 20q13. The highest allele-sharing LOD score was obtained on chromosome 18p (LOD = 2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q13 and 9q22. In the follow up analysis of the nine regions, including all 109 families, the highest allele-sharing LOD scores were obtained on chromosomes 5q, 13q and 18p although none reached the initial genome wide values. In paper III, we focused on the chromosome 5q region, and further mapping and haplotype analysis in the families was performed. A common 1 cM haplotype was found to be shared among affected members of five families. In this region only the regulatory subunit 1 of phosphatidylinositol 3-kinase (PIK3R1) gene was located. Association of three single nucleotide polymorphisms in the PIK3R1 gene to common stroke was obtained in the case-control material. Finally, in paper IV, an extended pedigree containing seven families connected to common founders eight generations back was identified by genealogical analysis, and submitted to a separate genome wide scan analysis. A significant allele-sharing LOD score of 4.66 (genome wide P < 0.001) at chromosome 9q31-33 was obtained. Haplotype analysis identified a minimal common region of 3.2 cM, which was shared by four of the seven families. These four families contained all of the primary intracerebral hemorrhagic cases present in the extended pedigree.

    In conclusion we have replicated linkage of stroke susceptibility to the PDE4D region on chromosome 5q, but no significant association of ischemic stroke to PDE4D was observed. Linkage analysis of stroke did not identify any new major stroke loci, indicating that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5q could contribute to the disease. In the chromosome 5q region a novel positional candidate gene for stroke was identified, the PIK3R1 gene. The PIK3R1 protein has several biological actions with potential roles in stroke susceptibility. Also a novel susceptibility locus for common forms of stroke at chromosome 9q was identified in a large pedigree, which may be of special importance for susceptibility to hemorrhagic stroke.

  • 180. Njølstad, Pål Rasmus
    et al.
    Andreassen, Ole Andreas
    Brunak, Søren
    Borglum, Anders D.
    Dillner, Joakim
    Esko, Tonu
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Radclife Department of Medicine, University of Oxford, Oxford, UK.
    Freimer, Nelson
    Groop, Leif
    Heimer, Hakon
    Hougaard, David M.
    Hovig, Eivind
    Hveem, Kristian
    Jalanko, Anu
    Kaprio, Jaakko
    Knudsen, Gun Peggy
    Melbye, Mads
    Metspalu, Andres
    Mortensen, Preben Bo
    Palmgren, Juni
    Palotie, Aarno
    Reed, Wenche
    Stefansson, Hreinn
    Stitziel, Nathan O.
    Sullivan, Patrick F.
    Thorsteinsdottir, Unnur
    Vaudel, Marc
    Vuorio, Eero
    Werge, Thomas
    Stoltenberg, Camilla
    Stefansson, Kari
    Roadmap for a precision-medicine initiative in the Nordic region2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 924-930Article in journal (Other academic)
    Abstract [en]

    The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.

  • 181.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Genetics of pain: studies of migraine and pain insensitivity2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pain is a major public health issue throughout the world. Increased understanding of the different forms of pain and identification of susceptibility genes could contribute to improved treatments. The main aims of this thesis were to identify the underlying genetic causes of pain by studying two large families affected with migraine and pain insensitivity, respectively.

    Migraine is one of the most common neurovascular disorders, affecting over 12% of the western population. The genetic contribution to migraine is about 50% according to family and twin studies. To identify novel susceptibility loci for migraine, we performed a genome-wide screen in a large family with migraine from northern Sweden. Linkage analysis revealed significant evidence of linkage (LOD=5.41) on chromosome 6p12.2-p21.1. A predisposing haplotype spanning 10 Mb was inherited with migraine in all affected members of the pedigree. Further fine-mapping of multiple SNP markers restricted the disease critical region to 8.5 Mb. Nine candidate genes were sequenced, revealing no disease-associated polymorphisms in SLC29A1, CLIC5, PLA2G7, IL17, SLC25A27 and TNFRSF21, but rare novel polymorphisms segregating with the disease haplotype in EFHC1, RHAG and MEP1A. EFHC1 has recently been shown to be involved in epilepsy, which is interesting considering the link between migraine and epilepsy. However, association analysis of EFHC1 revealed no difference between patients and controls, suggesting that this gene is not a risk factor for migraine. The combination of the two polymorphisms in RHAG and MEP1A could, however, not be found in any control individuals, indicating that they might be involved in genetic predisposition to migraine in this family.

    Disorders with reduced pain sensitivity are very rare, since pain perception is essential for survival. A number of disorders have still been identified with pain insensitivity and peripheral nerve degeneration as major clinical signs, including the hereditary sensory and autonomic neuropathies (HSAN). In order to identify novel susceptibility genes for HSAN V, we performed a genome-wide screen in a large consanguineous pedigree from a small village in northern Sweden. A homozygous region identical-by-descent was identified on chromosome 1p11.2-p13.2 in the three most severely affected patients. Subsequent analysis of candidate genes revealed a missense mutation in a conserved region of the nerve growth factor beta (NGFB) gene, causing a drastic amino acid change (R211W) in the NGF protein. NGF is important for the development and maintenance of the sympathetic and sensory nervous system and is therefore likely to be involved in disease. Functional analysis revealed that mutant NGF failed to induce neurite outgrowth and cell differentiation in PC12 cells. Furthermore, almost no mutant NGF was secreted by COS-7 cells, indicating that the processing and/or secretion of the protein might be disrupted.

    In conclusion, these findings present a novel migraine locus on chromosome 6 and identification of two rare polymorphisms that might be risk factors for migraine. Furthermore, a mutation in NGFB was found to cause complete loss of deep pain perception, which represents a very interesting model system to study pain mechanisms.

  • 182.
    Norberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Raaschou-Jensen, Klas
    Kjeldsen, Lars
    Moilanen, Jukka S.
    Paulsson-Karisson, Ylva
    Baliakas, Panagiotis
    Lohi, Olli
    Ahmed, Aymen
    Kittang, Astrid O.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Novel variants in Nordic patients referred for genetic testing of telomere-related disorders2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed)
    Abstract [en]

    Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

  • 183.
    Nordin, Angelica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Genetic and functional studies of hereditary myopathy with lactic acidosis2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML, OMIM#255125) is an autosomal recessive disorder which originates from Västerbotten and Ångermanland in the Northern part of Sweden. HML is characterized by severe exercise intolerance which manifests with tachycardia, dyspnea, muscle pain, cramps, elevated lactate and pyruvate levels, weakness and myoglobinuria. The symptoms arise from malfunction of the energy metabolism in skeletal muscles with defects in several important enzymes involved in the TCA cycle and the electron transport chain. All affected proteins contain iron-sulfur (Fe-S) clusters, which led to the suggestion that the disease was caused by malfunctions in either the transportation, assembly or processing of Fe-S clusters.

    The aim of my thesis was to identify the disease causing gene of HML and to investigate the underlying disease-mechanisms. In paper I we identified a disease-critical region on chromosome 12; a region containing 16 genes. One of the genes coded for the Fe-S cluster assembly protein ISCU and an intronic base pair substitution (g.7044G>C) was identified in the last intron of this gene. The mutation gave rise to the insertion of intron sequence into the mRNA, leading to a protein containing 15 abberant amino acids and a premature stop. In paper II we investigated why a mutation in an evolutionary well conserved protein with a very important cellular role, which in addition is expressed in almost all tissues, gives rise to a muscle-restricted phenotype. Semi-quantitative RT-PCR analysis showed that the mutant transcript constituted almost 80% of total ISCU mRNA in muscle, while in both heart and liver the normal splice form was dominant. We could also show that, in mice, complete absence of Iscu protein was coupled with early embryonic death, further emphasizing the importance of the protein in all tissues. These data strongly suggested that tissue-specific splicing was the main mechanism responsible for the muscle-specific phenotype of HML. In paper III the splicing mechanisms that give rise to the mutant ISCU transcript was further investigated. We identified three proteins; PTBP1, IGF2BP1 and RBM39, that could bind to the region containing the mutation and could affect the splicing pattern of ISCU in an in vitro system. PTBP1 repressed the inclusion of the intronic sequence, while IGF2BP1 and RBM39 repressed the total ISCU mRNA level though the effect was more pronounced for the normal transcript. Moreover, IGF2BP1 and RBM39 were also able to reverse the effect of PTBP1. IGF2BP1, though not a splicing factor, had higher affinity for the mutant sequence. This suggested that the mutation enables IGF2BP1 binding, thereby preventing the PTBP1 induced repression seen in the normal case.

    In conclusion, we have determined the genetic cause of HML, identifying a base pair substitution in the last intron of the ISCU gene that gives rise to abnormally spliced transcript. The muscle-specific phenotype was also analyzed and tissue-specific splicing was identified as the main disease-mechanism. Furthermore, nuclear factors with ability to affect the splicing pattern of the mutant ISCU gene were identified. This work has thoroughly investigated the fundamental disease mechanisms, thus providing deeper understanding for this hereditary myopathy.

  • 184.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Division of Neurology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsukeshi, Tochigi 329-0498, Japan.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Alstermark, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 11, p. 3133-3142Article in journal (Refereed)
    Abstract [en]

    A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found.

  • 185.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice2011In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 129, no 4, p. 371-378Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulphur cluster assembly gene (ISCU) leading to incorporation of intron sequence into the mRNA. This results in a deficiency of Fe-S cluster proteins, affecting the TCA cycle and the respiratory chain. The proteins involved in the Fe-S machinery are evolutionary conserved and shown to be fundamental in all organisms examined. ISCU is expressed at high levels in numerous tissues in mammals, including high metabolic tissues like the heart, suggesting that a drastic mutation in the ISCU gene would be damaging to all energy-demanding organs. In spite of this, the symptoms in patients with HML are restricted to skeletal muscle, and it has been proposed that splicing events may contribute to the muscle specificity. In this study we confirm that a striking difference in the splicing pattern of mutant ISCU exists between different tissues. The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart. The splicing differences were also reflected at a functional level, where loss of Fe-S cluster carrying enzymes and accumulation of iron were present in muscle, but absent in other tissues. We also show that complete loss of ISCU in mice results in early embryonic death. The mice data confirm a fundamental role for ISCU in mammals and further support tissue-specific splicing as the major mechanism limiting the phenotype to skeletal muscle in HML.

  • 186. Nordlund, Jessica
    et al.
    Backlin, Christofer L.
    Wahlberg, Per
    Busche, Stephan
    Berglund, Eva C.
    Eloranta, Maija-Leena
    Flaegstad, Trond
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Frost, Britt-Marie
    Harila-Saari, Arja
    Heyman, Mats
    Jonsson, Olafur G.
    Larsson, Rolf
    Palle, Josefine
    Ronnblom, Lars
    Schmiegelow, Kjeld
    Sinnett, Daniel
    Soderhall, Stefan
    Pastinen, Tomi
    Gustafsson, Mats G.
    Lonnerholm, Gudmar
    Syvanen, Ann-Christine
    Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 9, p. Article number: r105-Article in journal (Refereed)
    Abstract [en]

    Background: Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood. Results: We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. Conclusions: Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.

  • 187.
    Norgren, Nina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hereditary transthyretin amyloidosis (ATTR V30M): from genes to genealogy2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Hereditary transthyretin amyloidosis is an autosomal dominant disease with a reduced penetrance. The most common mutation in Sweden is the V30M mutation in the transthyretin gene. Clustering areas of the disease can be found in Northern Sweden, Portugal, Brazil and Japan, although sporadic cases exist worldwide. Despite being caused by the same mutation, there are large differences in onset, penetrance and symptoms of the disease. Swedish V30M patients typically have a later onset with a lower penetrance compared to those from the clustering Portuguese V30M areas. The reasons for these differences have not been fully understood. The aim of this thesis is to study mechanisms that may influence onset and symptoms and investigate why patients carrying the same mutation have different phenotypes.

    Methods: Genealogy studies were performed on all known V30M carriers in Sweden using standard genealogy methods. DNA samples from patients, asymptomatic carriers and controls from different countries were collected and the transthyretin gene was sequenced. Liver biopsies from patients were used for allele specific expression analysis and a cell assay was used for miRNA analysis with the mutated allele. Gene expression analysis was performed on biopsies from liver and fat from patients and controls.

    Results and conclusions: Genealogic analysis of all known Swedish V30M carriers managed to link together 73% of the Swedish ATTR V30M population to six different ancestors from the 17th and 18th century, thus dating the Swedish V30M mutation to be more than 400 years old. A founder effect was also visible in descendants to one of the ancestors, producing a later age at onset. Sequencing of the transthyretin gene revealed a SNP in the 3’ UTR of all Swedish V30M carriers that was not found in any of the Japanese or French V30M carriers. The SNP was present on the Swedish transthyretin haplotype and defined the Swedish V30M population as separate from others. However, the SNP itself had no effect upon phenotype or onset of disease. Gene expression analysis of liver and fat tissue revealed a change in genetic profile of the patients’ livers, in contrast to the unchanged profile of the fat tissue. A changed genetic profile of the liver could explain why domino liver recipients develop the disease much earlier than expected.

  • 188.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Andersson Escher, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Genealogic studies of the Swedish hereditary transthyretin amyloidosis (ATTR V30M) population: differences in age at onset within the populationManuscript (preprint) (Other academic)
  • 189.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mattson, Emma
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.32011In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 2, p. 137-143Article in journal (Refereed)
    Abstract [en]

    The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.

  • 190.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ericzon, Bo Goran
    de Tayrac, Marie
    Genin, Emmanuelle
    Plante-Bordeneuve, Violaine
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gene expression profile in hereditary transthyretin amyloidosis: differences in targeted and source organs2014In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 2, p. 113-119Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTR) is a genetic disease caused by a point mutation in the TTR gene that causes the liver to produce an unstable TTR protein. The most effective treatment has been liver transplantation in order to replace the variant TTR producing liver with one that produces only wild-type TTR. ATTR amyloidosis patients' livers are reused for liver sick patients, i.e. the Domino procedure. However, recent findings have demonstrated that ATTR amyloidosis can develop in the recipients within 7-8 years. The aim of this study was to elucidate how the genetic profile of the liver is affected by the disease, and how amyloid deposits affect target tissue. Methods: Gene expression analysis was used to unravel the genetic profiles of Swedish ATTR V30M patients and controls. Biopsies from adipose tissue and liver were examined. Results and Conclusions: ATTR amyloid patients' gene expression profile of the main source organ, the liver, differed markedly from that of the controls, whereas the target organs' gene expression profiles were not markedly altered in the ATTR amyloid patients compared to those of the controls. An impaired ER/protein folding pathway might suggest ER overload due to mutated TTR protein.

  • 191.
    Ny, Tor
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckman, Assar
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Enkvist, K
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Fredriksson, C
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Järvinen, S
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lund, B
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Isolation and characterization of the genomic region carrying the human tissue plasminogen activator gene1985In: Progress in Fibrinolysis. Vol. 7 / [ed] John Forsyth Davidsson, Churchill Livingstone , 1985, p. 205-207Chapter in book (Refereed)
  • 192.
    Ny, Tor
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Y-X
    Ohlsson, M
    Peng, X-R
    Jia, X-C
    Hsueh, A.J.W.
    Hormone regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 gene expression in the ovary1990In: Major advances in female reproduction / [ed] Adashi, E.Y. and Macuso, S., Raven press , 1990Chapter in book (Refereed)
  • 193.
    Ny, Tor
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ohlsson, Monica
    Strandberg, Leif
    The gene for t-PA1988In: Tissue-type plasminogen activator (t-PA): physiological and clinical aspects. Vol. 1 / [ed] Cornelis Kluft, CRC Press, 1988, p. 83-100Chapter in book (Refereed)
  • 194.
    Nylander, Per-Olof
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ethnic heterogeneity of the North-Swedish population: its origin and medical consequences1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Northern Sweden shows a unique population structure with remarkable geographical variations in the distribution of genetic disorders as well as genetic markers like blood groups, serum groups and red cell enzyme types. The present-day population of northern Sweden is a mixture of people of Finnish, Saamish (Lappish) and Central-Swedish origin.

    In this thesis the ethnic heterogeneity of the North-Swedish population (counties of Västerbotten and Norrbotten) was studied using genetic blood markers, and the epidemiological impact of the ethnic heterogeneity was exemplified by studying the geographical correlation between Finnish admixture and risk factors for cardiovascular diseases. The following results were found:

    1 Two new ethnic marker genes were discovered: the GC*1F allele (GC serum groups) for Saamish influence and the TF*C3 allele (transferrin serum groups) for Finnish influence.

    2 Regional gene frequency variations in the A1A2B0 blood groups, 6-phosphogluconate dehydrogenase (6-PGD) types and transferrin and GC serum groups were studied in a sample of 4100-5600 individuals from northern Sweden distributed according to birth place into 23 subpopulations. A significant regional heterogeneity was found in all systems. The ethnic marker genes (AB0*A2, GC*1F, TF*C3, PGD*C) showed clineal variations consistent with the expected patterns of Finnish and Saamish admixture.

    3 Finnish and Saamish admixture was estimated in the 23 subpopulations using AB0*A2,

    GC*1F and PGD*C as Saamish markers and TF*C3, TF*DCHI, TF*B0-1 and SODI*2 as Finnish markers. The Saamish admixture varied between 0 and 34% and was strongest in the northern and northwestern parts of northern Sweden. The Finnish influence varied between 0 and 84% and was strongest in the northern and northeastern parts of the area. The ethnic marker genes showed significant geographical intercorrelations.

    4 Hypercholesterolemia showed a significant heterogeneity between the 23 subpopulations, and there was a significant geographical covariation with the degree of Finnish admixture. These results are consistent with the hypothesis that Finnish genetic influence may contribute to the development of hypercholesterolemia and thereby to the increased rate of cardiovascular diseases found in northern Sweden.

    The results of this study suggest that in addition to the founder effect ethnic heterogeneity is an important determinant of the structure of the North-Swedish population.

  • 195. Oei, Ling
    et al.
    Hsu, Yi-Hsiang
    Styrkarsdottir, Unnur
    Eussen, Bert H
    de Klein, Annelies
    Peters, Marjolein J
    Halldorsson, Bjarni
    Liu, Ching-Ti
    Alonso, Nerea
    Kaptoge, Stephen K
    Thorleifsson, Gudmar
    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.
    Hocking, Lynne J
    Husted, Lise Bjerre
    Jameson, Karen A
    Kruk, Marcin
    Lewis, Joshua R
    Patel, Millan S
    Scollen, Serena
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Trompet, Stella
    van Schoor, Natasja M
    Zhu, Kun
    Buckley, Brendan M
    Cooper, Cyrus
    Ford, Ian
    Goltzman, David
    González-Macías, Jesús
    Langdahl, Bente Lomholt
    Leslie, William D
    Lips, Paul
    Lorenc, Roman S
    Olmos, José M
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Reid, David M
    Riancho, José A
    Slagboom, P Eline
    Garcia-Ibarbia, Carmen
    Ingvarsson, Thorvaldur
    Johannsdottir, Hrefna
    Luben, Robert
    Medina-Gómez, Carolina
    Arp, Pascal
    Nandakumar, Kannabiran
    Palsson, Stefan Th
    Sigurdsson, Gunnar
    van Meurs, Joyce B J
    Zhou, Yanhua
    Hofman, Albert
    Jukema, J Wouter
    Pols, Huibert A P
    Prince, Richard L
    Cupples, L Adrienne
    Marshall, Christian R
    Pinto, Dalila
    Sato, Daisuke
    Scherer, Stephen W
    Reeve, Jonathan
    Thorsteinsdottir, Unnur
    Karasik, David
    Richards, J Brent
    Stefansson, Kari
    Uitterlinden, André G
    Ralston, Stuart H
    Ioannidis, John P A
    Kiel, Douglas P
    Rivadeneira, Fernando
    Estrada, Karol
    A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus2014In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 2, p. 122-131Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

    AIM: To identify CNVs associated with osteoporotic bone fracture risk.

    METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.

    RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.

    CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

  • 196. Ohta, Yasuyuki
    et al.
    Soucy, Genevieve
    Phaneuf, Daniel
    Audet, Jean-Nicolas
    Gros-Louis, Francois
    Rouleau, Guy A.
    Blasco, Helene
    Corcia, Philippe
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Univ Ulm, Dept Neurol, Ulm, Germany.
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Yamashita, Toru
    Abe, Koji
    Julien, Jean-Pierre
    Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 21, p. 4771-4786Article in journal (Refereed)
    Abstract [en]

    Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

  • 197. Olofsson, P
    et al.
    Söderström, L
    Jern, C
    Sirsjö, A
    Ria, M
    Sundler, E
    de Faire, U
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ohrvik, J
    Hedin, U
    Paulsson-Berne, G
    Hamsten, A
    Eriksson, P
    Hansson, G
    Genetic variants of TNFSF4 and risk for carotid artery disease and stroke2008In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 87, no 4, p. 337-346Article in journal (Refereed)
    Abstract [en]

    In two independent human cohorts, the minor allele of SNP rs3850641 in TNFSF4 was significantly more frequent in individuals with myocardial infarction than in controls. In mice, Tnfsf4 expression is associated with increased atherosclerosis. The expression of TNFSF4 in human atherosclerosis and the association between genotype and cerebrovascular disease have not yet been investigated. TNFSF4 messenger RNA (mRNA) levels were significantly higher in human atherosclerotic lesions compared with controls (730 +/- 30 vs 330 +/- 65 arbitrary units, p < 0.01). TNFSF4 was mainly expressed by macrophages in atherosclerotic lesions. In cell culture, endothelial cells upregulated TNFSF4 in response to tumor necrosis factor alpha (TNF-alpha; 460 +/- 110 vs 133 +/- 8 arbitrary units, p < 0.001 after 6 h of stimulation). We analyzed the TNFSF4 gene in 239 patients who had undergone carotid endarterectomy and 138 matching controls from The Biobank of Karolinska Carotid Endarterectomies and Stockholm Heart Epidemiology Program cohorts and 929 patients and 1,382 matching controls from the Sahlgrenska Academy Study on Ischemic Stroke and Case Control Study of Stroke cohorts, limiting inclusion to patients with ischemic stroke. Participants were genotyped for the rs3850641 SNP in TNFSF4. Genotype associations were neither found with TNFSF4 mRNA levels nor with atherosclerosis associated systemic factors or risk for stroke. This study shows that TNFSF4 is expressed on antigen-presenting cells in human carotid atherosclerotic lesions but provides no evidence for an association of TNFSF4 gene variation with the risk for ischemic stroke.

  • 198. Olofsson, Peter
    et al.
    Nerstedt, Annika
    Hultqvist, Malin
    Nilsson, Elisabeth C
    Andersson, Sofia
    Bergelin, Anna
    Biovitrum AB, Göteborg, Sweden.
    Holmdahl, Rikard
    Arthritis suppression by NADPH activation operates through an interferon-beta pathway2007In: BMC Biology, ISSN 1741-7007, E-ISSN 1741-7007, Vol. 5, p. 19-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A polymorphism in the activating component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (NCF1), has previously been identified as a regulator of arthritis severity in mice and rats. This discovery resulted in a search for NADPH oxidase-activating substances as a potential new approach to treat autoimmune disorders such as rheumatoid arthritis (RA). We have recently shown that compounds inducing NCF1-dependent oxidative burst, e.g. phytol, have a strong ameliorating effect on arthritis in rats. However, the underlying molecular mechanism is still not clearly understood. The aim of this study was to use gene-expression profiling to understand the protective effect against arthritis of activation of NADPH oxidase in the immune system.

    RESULTS: Subcutaneous administration of phytol leads to an accumulation of the compound in the inguinal lymph nodes, with peak levels being reached approximately 10 days after administration. Hence, global gene-expression profiling on inguinal lymph nodes was performed 10 days after the induction of pristane-induced arthritis (PIA) and phytol administration. The differentially expressed genes could be divided into two pathways, consisting of genes regulated by different interferons. IFN-gamma regulated the pathway associated with arthritis development, whereas IFN-beta regulated the pathway associated with disease protection through phytol. Importantly, these two molecular pathways were also confirmed to differentiate between the arthritis-susceptible dark agouti (DA) rat, (with an Ncf-1DA allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-1E3 rat (with an Ncf1E3 allele that allows a stronger oxidative burst).

    CONCLUSION: Naturally occurring genetic polymorphisms in the Ncf-1 gene modulate the activity of the NADPH oxidase complex, which strongly regulates the severity of arthritis. We now show that the Ncf-1 allele that enhances oxidative burst and protects against arthritis is operating through an IFN-beta-associated pathway, whereas the arthritis-driving allele operates through an IFN-gamma-associated pathway. Treatment of arthritis-susceptible rats with an NADPH oxidase-activating substance, phytol, protects against arthritis. Interestingly, the treatment led to a restoration of the oxidative-burst effect and induction of a strikingly similar IFN-beta-dependent pathway, as seen with the disease-protective Ncf1 polymorphism.

  • 199.
    Olsson, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect2008In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 11, p. 1666-1672Article in journal (Refereed)
    Abstract [en]

    We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.

  • 200. Olsson, Linda
    et al.
    Lundin-Ström, Kristina B.
    Castor, Anders
    Behrendtz, Mikael
    Biloglav, Andrea
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Paulsson, Kajsa
    Johansson, Bertil
    Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis: A single center experience of 296 cases2018In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 57, no 11, p. 604-607Article in journal (Refereed)
    Abstract [en]

    Single nucleotide polymorphism array (SNP‐A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP‐A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T‐cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP‐A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G‐banding. Of 260 B‐cell precursor (BCP) ALL cases, SNP‐A analyses identified additional copy number alterations, including the above‐mentioned microdeletions, or better characterized the imbalances found by G‐banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP‐A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype‐specific minimal residual disease stratification. We conclude that SNP‐A analyses dramatically improve the cytogenetic characterization of both T‐cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.

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