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

Jonas B. Nielsen, Lars G. Fritsche, Wei Zhou, Tanya M. Teslovich, Oddgeir L. Holmen, Stefan Gustafsson, Maiken E. Gabrielsen, Ellen M. Schmidt, Robin Beaumont, Brooke N. Wolford, Maoxuan Lin, Chad M. Brummett, Michael H. Preuss, Lena Refsgaard, Erwin P. Bottinger, Sarah E. Graham, Ida Surakka, Yunhan Chu, Anne Heidi Skogholt, Håvard DalenAlan P. Boyle, Hakan Oral, Todd J. Herron, Jacob Kitzman, José Jalife, Jesper H. Svendsen, Morten S. Olesen, Inger Njølstad, Maja Lisa Løchen, Aris Baras, Omri Gottesman, Anthony Marcketta, Colm O'Dushlaine, Marylyn D. Ritchie, Tom Wilsgaard, Ruth J.F. Loos, Timothy M. Frayling, Michael Boehnke, Erik Ingelsson, David J. Carey, Frederick E. Dewey, Hyun M. Kang, Gonçalo R. Abecasis, Kristian Hveem, Cristen J. Willer

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)103-115
Number of pages13
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2018

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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