Common genetic variants associated with characteristics and clinical outcomes of atrial fibrillation: from a large population based registry (FinnGen)

Abstract Background Atrial Fibrillation (AF) in younger patients without coexisting structural heart disease is believed to be mediated by genetic causes; however data on genetic associations from large registries are limited. Methods We obtained de-identified data from the FinnGen registry, which is a national census-based registry with available data on genetic variants from participants in Finland. Imputed genetic variants from microarray data including common genetic variants across cases and controls were analyzed by GWAS, and further fine-mapping of causal SNPs to gene-level, miRNA-level, and pathway-level association was performed. The diagnosis of AF was derived from the International Classification of Disease-10 (ICD) codes. Results The total sample size in Finn-Gen registry was 500,348 participants, amongst those 56.4% were females. The median age of AF-onset in females was 71.8 vs. 68.7 years in males. Upon analysis of participants with available genetic data, there were a total of 21,323,076 imputed genetic variants across 63,532 cases with AF and 252,810 controls. There were a total of 7,619 significant SNPs in GWAS which mapped to 183 enriched unique loci across 142 genes, including most strongly to loci in chromosomes 16 (near ZFHX3, 989 SNPs), 1 (KCND3, KCCN3, 759 SNPs), 7 (CAV1, 119 SNPs), and chromosome 4 (PITX2, LINC01438, 111 SNPs) (Figure 1). Additional gene-level analysis implicated 313 genes including both previously characterized and novel markers such as SCN5A, TBX5, TTN, and ELOVL6. Pathway-level association of significant genes were consistent with AF-related biological processes such as cardiac conduction within His-Purkinje cells, action potential generation, repolarization, actin-mediated cell contraction, potassium channel activity, and hyperaldosteronism. Two micro-RNA hsa-miR-204 and hsa-miR-211 were identified as potential key regulators of AF-associated genes from the study. After excluding the participants who had structural heart disease, the highest degree of genetic colocalization (as assessed by "Colocalization hits") was evident for the coexisting diagnosis of hypertension (HTN), cardioembolic stroke. During the follow-up of 21 years, between 01/1998 and 12/2019; AF diagnosis was associated with an increased risk of mortality in both men and women. The effect size of AF diagnosis and overall mortality was stronger in men (adjusted HR of 2.01, 95% CI: 1.84-2.19, p 0.001) in comparison with women (adjusted HR of 1.87, 95% CI: 1.72-2.02, p 0.001). Conclusions In a large epidemiological database (FinnGen), the diagnosis of atrial fibrillation was associated with a polygenic pattern of association across several genes including ZFHX3, KCND3, CAV1, PITX2, SCN5A, and TTN and biological processes. Over a relatively longer period of follow up of 21 years, the diagnosis of AF was associated with an increased risk of mortality in both men and women.Manhattan plot of AF-GWAS