Journal Article

Biobank-driven genomic discovery yields new insight into atrial fibrillation biology

Dey, Rounak, Wolford, Brooke N., Abecasis, Gonçalo R., Skogholt, Anne Heidi, Teslovich, Tanya M., Jalife, José, Crawford, Ryan D., Backman, Joshua D., Mukherjee, Bhramar, Hveem, Kristian, O’Dushlaine, Colm, Skov, Morten W., Dalen, Håvard, Fritsche, Lars G., Kitzman, Jacob, Stefansson, Kari, Thorolfsdottir, Rosa B., Herron, Todd J., Baras, Aris, Wen, Xiaoquan, Lee, Seunggeun, McCarthy, Shane, Brummett, Chad M., Yamazaki, Masatoshi, Boehnke, Michael, Carey, David J., Holst, Anders G., Kheterpal, Sachin, Gabrielsen, Maiken E., Chung, Jonathan H., Shavit, Jordan A., Sveinbjornsson, Gardar, Hornsby, Whitney, Thorsteinsdottir, Unnur, Holmen, Oddgeir L., Willer, Cristen J., Arnar, David O., Schmidt, Ellen M., Nielsen, Jonas B., Dewey, Frederick E., Holm, Hilma, Kang, Hyun M., Gudbjartsson, Daniel F., Mathis, Michael R., Graham, Sarah E., Sulem, Patrick, Zhou, Wei, Surakka, Ida, Lin, Maoxuan

2018

Overview

To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans ( GATA4, MYH6 , NKX2-5 , PITX2 , TBX5 ) 1 , or near genes important for striated muscle function and integrity (for example, CFL2 , MYH7 , PKP2, RBM20, SGC G, SSPN ). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an ‘atrial cardiomyopathy’ 2 , either during fetal heart development or as a response to stress in the adult heart. Large-scale association analyses identify 142 independent risk variants for atrial fibrillation. Pathway and functional enrichment analyses suggest that many of the putative risk genes act via cardiac structural remodeling.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/22 / 45/23 / 45/43 / 631/208/191/2018 / 631/208/205/2138 / 692/699/75/29/1309 / Accidental falls / Agriculture / Animal Genetics and Genomics / Arrhythmia / Atrial fibrillation / Binding sites / Biology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiac arrhythmia / Cardiomyopathy / Computational biology / Consortia / Developmental biology / Discovery and exploration / Fetuses / Fibrillation / Gene expression / Gene Function / Genes / Genetic aspects / Genetic diversity / Genetic research / Genomes / Genomics / Heart / Human Genetics / Informatics / Letter / Mediation / Muscles / Mutation / Myocardial diseases / Nkx2.5 protein / Proteins / Skeletal muscle / Studies