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

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

doi:10.1016/j.ajhg.2017.12.003

Cited by 88 publications

(69 citation statements)

References 76 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There is a significant association between common variants at the TTN locus and AF in other studies. 7,32,34,35 The direction and effect size of the association observed in the current study is similar to that previously reported, but the differences observed in statistical significance may be a reflection of the sample size. In the common variant analysis, there was an association between individuals with early-onset AF and genetic variants at the NAV2 locus, a finding that was observed in two recent meta-analyses for AF.…”

Section: Discussionsupporting

confidence: 90%

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Choi¹,

Weng²,

Roselli³

et al. 2018

JAMA

Self Cite

150

133

View full text Add to dashboard Cite

Importance Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective To perform large-scale, deep-coverage whole genome sequencing to identify genetic variants related to AF. Design, Setting, Participants The National Heart Lung and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high depth, whole genome sequencing between 2014 and 2017 in 18,526 individuals from the U.S., Mexico, Puerto-Rico, Costa-Rica, Barbados, and Samoa. This case-control study included 2,781 patients with early onset AF from 9 studies and identified 4,959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank and the MyCode Study consisting of 346,546 and 42,782 participants, respectively. Exposures Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures Early-onset AF defined as AF onset < 66 years of age. Due to multiple testing, the significance threshold for the rare variant analysis was P=4.55 X 10−3. Results Among 2,781 early-onset AF cases, 72.1% were male, and the mean age of AF onset was 48.7±10.2 years. Samples underwent whole genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least one LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of cases compared with 1.1% in controls. The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend 4.92×10−4) and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (odds ratio = 5.94; 95% CI, 2.64–13.35; P=1.65×10−5). The association between TTN LOF variants and AF was replicated in an independent 1,582 early-onset AF cases and 41,200 controls (odds ratio = 2.16; 95% CI, 1.19–3.92; P=0.01). Conclusions and Relevance In a case control study, there was a statistically significant association between a LOF variant in the gene TTN and early-onset AF, with the variant present in a small percentage of cases. Further research is required to understand whether this is a causal relationship.

show abstract

Section: Discussionsupporting

confidence: 90%

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Choi¹,

Weng²,

Roselli³

et al. 2018

JAMA

Self Cite

150

133

View full text Add to dashboard Cite

show abstract

“…These findings are in line with recent reports which have linked AF with rare coding variants in the sarcomere genes MYH6 and MYL4 and in the multidomain cyto-skeletal linking protein PLEC along with more common coding variants in TTN, essential for the passive elasticity of heart and skeletal muscle. 8,9,6,10 Although we could identify protein-altering variants at n = 21 loci, comprising either the index variant (n = 2 loci) or a variant in high linkage disequilibrium (LD) (r 2 ) with the index variant (n = 19 loci; Supplementary Table 8), we noted that most associated risk variants are in the non-coding genome (159 of 163 independent risk variants). To assess the potential function of associated non-coding variants, we tested for enrichment of AF-associated variants with a variety of regulatory features including DNase I hypersensitive sites (DHS), histone methylation marks, transcription factor binding sites, and chromatin states in a variety of cell and tissue types available from Roadmap Epigenomics 11 using 'Genomic Regulatory Elements and Gwas Overlap algoRithm' (GREGOR).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryTo understand the genetic variation underlying atrial fibrillation (AF), the most common cardiac arrhythmia, we performed a genome-wide association study (GWAS) of > 1 million people, including 60,620 AF cases and 970,216 controls. We identified 163 independent risk variants at 111 loci and prioritized 165 candidate genes likely to be involved in AF. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans or mice (MYH6, NKX2-5, PITX2, TBC1D32, TBX5),1,2 or near genes important for striated muscle function and integrity (e.g. MYH7, PKP2, SSPN, SGCA). Experiments in rabbits with heart failure and left atrial dilation identified a heterogeneous distributed molecular switch from MYH6 to MYH7 in the left atrium, which resulted in contractile and functional heterogeneity and may predispose to initiation and maintenance of atrial arrhythmia.

show abstract

“…We performed look-ups for each lead variant or their proxies (r 2 >0.8) for associations (P<5×10 −8 ) for common traits using both GWAS catalog 57 and PhenoScanner v2 58 databases. For AF, we supplemented the variant listing with a manually curated list of all overlapping variants (r 2 >0.7) with PR interval from two recently published GWASs 59,60 .…”

Section: Methodsmentioning

confidence: 99%

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Ντάλλα

Weng

Cartwright

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

show abstract

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

Cited by 88 publications

References 76 publications

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Contact Info

Product

Resources

About