Atrial fibrillation (AF) affects over 33 million individuals worldwide1 and has a complex heritability.2 We conducted the largest meta-analysis of genome-wide association studies for AF to date, consisting of over half a million individuals including 65,446 with AF. In total, we identified 97 loci significantly associated with AF including 67 of which were novel in a combined-ancestry analysis, and 3 in a European specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait loci (eQTL) analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10−64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10−58) and docosapentaenoic acid (DPA, p = 4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10−12) and DPA (p = 1×10−43) and lower docosahexaenoic acid (DHA, p = 1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death.1,2 Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups.3–7 To further define the genetic basis of atrial fibrillation, we performed large-scale, multi-racial meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 18,398 individuals with atrial fibrillation and 91,536 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,806 cases and 132,612 referents. We identified 12 novel genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate new potential targets for drug discovery.8

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.