Potential etiologic and functional implications of genome-wide association loci for human diseases and traits

TLDR

The authors present an online catalog of SNP‑trait associations and functional predictions to aid future studies of common variant contributions to complex disease etiology. They compiled the catalog from published GWAS to examine genomic features of trait/disease‑associated SNPs. The catalog reveals that trait‑associated SNPs are common (median risk allele frequency 36%) with modest effect sizes (median OR 1.33), are enriched in nonsynonymous and promoter regions, depleted in intergenic regions, and show only marginal enrichment for positive selection.

Abstract

We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). Reported TASs were common [median risk allele frequency 36%, interquartile range (IQR) 21%−53%] and were associated with modest effect sizes [median odds ratio (OR) 1.33, IQR 1.20–1.61]. Among 20 genomic annotation sets, reported TASs were significantly overrepresented only in nonsynonymous sites [OR = 3.9 (2.2−7.0), p = 3.5 × 10 −7 ] and 5kb-promoter regions [OR = 2.3 (1.5−3.6), p = 3 × 10 −4 ] compared to SNPs randomly selected from genotyping arrays. Although 88% of TASs were intronic (45%) or intergenic (43%), TASs were not overrepresented in introns and were significantly depleted in intergenic regions [OR = 0.44 (0.34−0.58), p = 2.0 × 10 −9 ]. Only slightly more TASs than expected by chance were predicted to be in regions under positive selection [OR = 1.3 (0.8−2.1), p = 0.2]. This new online resource, together with bioinformatic predictions of the underlying functionality at trait/disease-associated loci, is well-suited to guide future investigations of the role of common variants in complex disease etiology.