@article{5cbb7c736ce3452e8f161126d902a999,
title = "Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development",
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 × 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 × 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.",
author = "Nielsen, {Jonas B.} and Fritsche, {Lars G.} and Wei Zhou and Teslovich, {Tanya M.} and Holmen, {Oddgeir L.} and Stefan Gustafsson and Gabrielsen, {Maiken E.} and Schmidt, {Ellen M.} and Robin Beaumont and Wolford, {Brooke N.} and Maoxuan Lin and Brummett, {Chad M.} and Preuss, {Michael H.} and Lena Refsgaard and Bottinger, {Erwin P.} and Graham, {Sarah E.} and Ida Surakka and Yunhan Chu and Skogholt, {Anne Heidi} and H{\aa}vard Dalen and Boyle, {Alan P.} and Hakan Oral and Herron, {Todd J.} and Jacob Kitzman and Jos{\'e} Jalife and Svendsen, {Jesper H.} and Olesen, {Morten S.} and Inger Nj{\o}lstad and L{\o}chen, {Maja Lisa} and Aris Baras and Omri Gottesman and Anthony Marcketta and Colm O'Dushlaine and Ritchie, {Marylyn D.} and Tom Wilsgaard and Loos, {Ruth J.F.} and Frayling, {Timothy M.} and Michael Boehnke and Erik Ingelsson and Carey, {David J.} and Dewey, {Frederick E.} and Kang, {Hyun M.} and Abecasis, {Gon{\c c}alo R.} and Kristian Hveem and Willer, {Cristen J.}",
note = "Funding Information: The Nord-Tr{\o}ndelag Health (HUNT) Study is a collaboration among the HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology), the Nord-Tr{\o}ndelag County Council, the Central Norway Health Authority, and the Norwegian Institute of Public Health. The HUNT-MI study, which comprises the genetic investigations of the HUNT Study, is a collaboration between investigators from the HUNT Study and the University of Michigan School of Public Health and the University of Michigan Medical School. The authors wish to thank all study participants who contributed to the scientific research. J.B.N. was supported by grants from the Danish Heart Foundation , the Lundbeck Foundation , the A.P M{\o}ller Foundation for the Advancement of Medical Science , and Fondsb{\o}rsvekselerer Henry Hansen og Hustru Karla Hansen F{\o}dt Vestergaards Legat . C.J.W. was supported by grants HL109946 , HL127564 , and HL130705 from the National Institutes of Health (NIH). J.H.S. and M.S.O. were supported by grants from the Danish National Research Foundation , the John and Birthe Meyer Foundation , the Arvid Nilsson Foundation , and the Research Council of Rigshospitalet, Denmark . E.I. was supported by the NIH ( 1R01DK106236-01A1 and 1R01HL135313-01 ), the Knut och Alice Wallenberg Foundation ( 2013.0126 ), the Swedish Heart-Lung Foundation ( 20140422 ), and the G{\"o}ran Gustafsson Foundation . Finally, this research was conducted with the UK Biobank Resource under application number 13721. ",
year = "2018",
month = jan,
day = "4",
doi = "10.1016/j.ajhg.2017.12.003",
language = "English (US)",
volume = "102",
pages = "103--115",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",
}