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Author (up) Nielsen, J.B.; Fritsche, L.G.; Zhou, W.; Teslovich, T.M.; Holmen, O.L.; Gustafsson, S.; Gabrielsen, M.E.; Schmidt, E.M.; Beaumont, R.; Wolford, B.N.; Lin, M.; Brummett, C.M.; Preuss, M.H.; Refsgaard, L.; Bottinger, E.P.; Graham, S.E.; Surakka, I.; Chu, Y.; Skogholt, A.H.; Dalen, H.; Boyle, A.P.; Oral, H.; Herron, T.J.; Kitzman, J.; Jalife, J.; Svendsen, J.H.; Olesen, M.S.; Njolstad, I.; Lochen, M.-L.; Baras, A.; Gottesman, O.; Marcketta, A.; O'Dushlaine, C.; Ritchie, M.D.; Wilsgaard, T.; Loos, R.J.F.; Frayling, T.M.; Boehnke, M.; Ingelsson, E.; Carey, D.J.; Dewey, F.E.; Kang, H.M.; Abecasis, G.R.; Hveem, K.; Willer, C.J. url  doi
  Title Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development Type Journal Article
  Year 2018 Publication American Journal of Human Genetics Abbreviated Journal Am J Hum Genet  
  Volume 102 Issue 1 Pages 103-115  
  Keywords Atrial Fibrillation/*genetics; *Genetic Loci; *Genetic Predisposition to Disease; *Genome-Wide Association Study; Heart/*embryology; Humans; Inheritance Patterns/genetics; Multifactorial Inheritance/genetics; Organ Specificity/genetics; Physical Chromosome Mapping; Quantitative Trait Loci/genetics; Regulatory Sequences, Nucleic Acid/*genetics; Reproducibility of Results; Risk Factors; *Cdkn2c; *Dmrta2; *Gwas; *Ttn; *atrial fibrillation; *cardiomyopathy; *fetal; *genetic risk score; *heart; *pathway  
  Abstract Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 x 10(-18)) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 x 10(-11)) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.  
  Address Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: cristen@umich.edu  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0002-9297 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29290336; PMCID:PMC5777936 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2143  
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