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.