Noncoding Genetic Variation and Gene Expression
Deciphering the Molecular Drivers of Genome-Wide Association Study Signals in Atrial Fibrillation
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See Article by Hsu et al
Robust familial and large-scale population-based epidemiological studies have firmly established a heritable contribution to the risk of developing atrial fibrillation (AF).1–4 The underlying mechanisms responsible for this heritability are complex, with evidence supporting the involvement of both rare and common genetic variants.5,6 Although considerable progress has been made since the first genetic culprit for AF was identified in 2003, translating our improved genetic understanding into clinically actionable treatment strategies remains a vision rather than a reality.7,8 Leveraging insights gleaned from rare variants identified in familial AF cases may be limited by their generalizability to the greater AF population, whereas a major challenge faced with common variants identified through genome-wide association studies (GWAS) has been clarifying their functional relevance. Single nucleotide polymorphisms (SNPs) identified through GWAS have been predominantly nonprotein coding, leaving experts to hypothesize their mechanism of action.9
As the list of AF GWAS SNPs progressively expands, there is a mounting need to clarify their functional effects to translate their identification into clinically actionable tools.10,11 The predominant belief has been that these SNPs reside within regulatory regions that modulate expression of nearby (and potentially remote) genes. Genomic loci that associate with altered mRNA expression levels are referred to as expression quantitative trait loci (eQTLs), with the terms cis and trans indicating regulation of nearby and distant genes, respectively.12 Notably, regulation of gene expression varies across cell types, and hence eQTL values are tissue-specific, a notion highlighting the importance of evaluating disease-associated SNPs in a disease-relevant tissue context. Given the limited availability of many human tissue types, a large-scale National Institutes of …