Connecting the Dots From GWAS to Function in Atrial Fibrillation for ZFHX3

Abstract

enetics significantly influence susceptibility to atrial fibrillation (AF). Individuals with first-degree relatives under 60 years old with AF have ≈5× higher risk 1 with heritability estimated at 22%. 2 Genetic burden can be divided into 2 main categories: rare variants with strong effects, often due to loss of function mutations, and common variants (most often single nucleotide polymorphisms, SNPs) that can additively increase AF susceptibility. Common AF-associated variants are identified by genome-wide association studies (GWAS). The first published GWAS of AF in 2007 reported SNPs on 4q25 near PITX2. 1 In 2010 variants near ZHFX3 (zinc finger homeobox 3) were identified. 2 With increasing cohort size, over 100 AF risk loci have now been identified. 3 However, despite advancements in genomics, our understanding of the pathological mechanisms of AF remains nebulous. Article, see p 313Polygenic risk scores for AF, using tens to millions of common variants, estimate that individuals in the top percentile have 4.6-fold increased risk of AF. 4 Exome sequencing in ≈43 000 UK Biobank subjects revealed that common variants explain >20-fold more of the AF variance than the rare variants. 5 Thus, GWAS identify the loci responsible for most of the population-attributable genetic risk for AF. GWAS loci, using Manhattan plots, display variants at each locus with ascending significance by P value. Most of these variants are a result of linkage disequilibrium (LD), implying they are often inherited together from ancestral chromosomes. However, discovering these loci is just the first step in the arduous tasks of identifying the responsible gene, variant(s), and mechanism for disease association.