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.
Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death1. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 1 0,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
Background
Chronic kidney disease (CKD) is associated with the incidence of cardiovascular disease. CKD may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results.
Methods and Results
We estimated cystatin C-based glomerular filtration rate (eGFRcys) and measured urinary albumin-creatinine ratio (ACR) in 10,328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996–98. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared to individuals with eGFRcys ≥90 mL/min/1.73 m2, multivariable hazard ratios (HR) and 95% confidence intervals (CI) of AF were 1.3 (1.1–1.6), 1.6 (1.3–2.1), and 3.2 (2.0–5.0) (p for trend <0.0001) in those with eGFRcys of 60–89, 30–59 and 15–29 mL/min/1.73 m2, respectively. Similarly, presence of macroalbuminuria (ACR ≥300 mg/g, HR 3.2, 95% CI 2.3–4.5) and microalbuminuria (ACR 30–299 mg/g, HR 2.0, 95% CI 1.6–2.4) were associated with higher AF risk compared to those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFRcys and macroalbuminuria (HR 13.1, 95% CI 6.0–28.6, comparing individuals with ACR≥300 mg/g and eGFRcys 15–29 vs. ACR<30 mg/g and eGFRcys ≥90 mL/min/1.73 m2).
Conclusion
In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors.
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