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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.

SUBMITTER: Nielsen JB 

PROVIDER: S-EPMC5777936 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development.

Nielsen Jonas B JB   Fritsche Lars G LG   Zhou Wei W   Teslovich Tanya M TM   Holmen Oddgeir L OL   Gustafsson Stefan S   Gabrielsen Maiken E ME   Schmidt Ellen M EM   Beaumont Robin R   Wolford Brooke N BN   Lin Maoxuan M   Brummett Chad M CM   Preuss Michael H MH   Refsgaard Lena L   Bottinger Erwin P EP   Graham Sarah E SE   Surakka Ida I   Chu Yunhan Y   Skogholt Anne Heidi AH   Dalen Håvard H   Boyle Alan P AP   Oral Hakan H   Herron Todd J TJ   Kitzman Jacob J   Jalife José J   Svendsen Jesper H JH   Olesen Morten S MS   Njølstad Inger I   Løchen Maja-Lisa ML   Baras Aris A   Gottesman Omri O   Marcketta Anthony A   O'Dushlaine Colm C   Ritchie Marylyn D MD   Wilsgaard Tom T   Loos Ruth J F RJF   Frayling Timothy M TM   Boehnke Michael M   Ingelsson Erik E   Carey David J DJ   Dewey Frederick E FE   Kang Hyun M HM   Abecasis Gonçalo R GR   Hveem Kristian K   Willer Cristen J CJ  

American journal of human genetics 20171228 1


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,  ...[more]

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