AF Genome Wide Association Analysis
Notably, the identification of mutations derived from linkage analyses is relatively uncommon, and most often found in patients with early-onset lone AF (<40-45 years of age at AF onset) and have a relatively small impact on population-level AF.29,30To interrogate more common variants that contribute to AF, GWAS studies compare patients with AF and unaffected controls and have identified SNPs that associate with increased risk of AF development. To date, over 100 loci have been identified to have genome-wide significance in AF risk, the majority of which have been studied in large populations of patients predominantly of European ancestry. Large cohort studies have revealed that European ancestry subjects have an increased risk of AF when compared to African, Asian, and Hispanic ancestry subjects, which suggests that these populations have different risk alleles or that the frequency of risk alleles differs significantly between groups.31-34 The largest multi-ethnic meta-analysis of GWAS for AF to-date had 84% European ancestry and identified 97 loci associated with AF, including 67 that were novel in a combined ancestry analysis and 3 that were European-specific.29 The region that was most significantly associated with AF across ancestries was 4q25, upstream of the PITX2 gene. Effect estimates were similar for the top associations, suggesting that genetic susceptibility for AF is relatively constant across ancestries. However, this meta-analysis with more than half a million participants only included 43,000 non-European subjects, with Asian ancestry most represented and Hispanic the least. Asian ancestry-specific GWAS have replicated some of these loci including PITX2 , TBX5 (which is associated with fibroblast differentiation)35 and ZFHX3 (a zinc finger-encoding gene associated with cellular differentiation located at 16q22), were found to be associated with early onset AF.36,37 However, in a small Hispanic/Latino cohort, of the 9 AF risk SNPs examined, only PITX2 replicated, highlighting the complex heterogeneity in AF genetics.38 There is a pressing need to improve diversity in studies of AF. Many loci are similar across ancestries, but prevalence and outcomes differ suggesting that shared loci may provide general disease mechanisms and unique loci may modify disease based on diverse genetic backgrounds or environmental effects. Efforts are underway to improve diversity in genetic studies including expansion of biobanks in China and Africa. In the US, programs such as the National Heart, Lung, and Blood Institute’s TOPMed Program, the Million Veteran Program, and the All of Us Research Program are trying to address these disparities in genetic studies.
Despite this, GWAS analyses have identified multiple genes associated with increased AF risk that are implicated in various aspects of cardiac myocyte function. SNPs located in genes encoding ion channels, includingKCNQ1 39,40, and the angiotensinogen gene (AGT )411 have been associated with increased risk of AF. Additionally, the 4q25 locus has consistently been strongly associated with AF risk in all-comers42, lone AF43, and new AF after coronary artery bypass surgery.44 The 4q25 locus is an inter-codon region near the gene for transcription factor PITX2 . This gene is known to regulate right-left differentiation in embryonic cardiac development.45 Additionally, PITX2overexpression leads to modification of L-type calcium and delayed rectifier potassium current, resulting in increased AF susceptibility through multiple pathways.46 Presence of multiple alleles in 4q25 is associated with a risk gradient for AF development47 and has been demonstrated to increase the likelihood of AF development in family members with rare genetic AF-associated variants.48 This suggests that other identified AF-associated SNPs may modulate AF development in those with rare, AF-associated mutations.