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

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 x 10(-7)] and 5kb-promoter regions [OR = 2.3 (1.5-3.6), p = 3 x 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 x 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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Published odds ratios for discrete traits by reported risk allele frequencies. Labeled SNP-trait associations are those with the highest ORs. Note that the y axis is on the log scale.

Fig. 2.

Odds ratios for TAS block enrichment/depletion analysis after adjusting for “hitchhiking” effects from nonsynonymous sites. Four annotation sets (Splice sites, Validated enhancers, EvoFold elements, and noncoding RNAs) are not represented here because no TAS blocks mapped to these annotation sets. The blue circle represents the point estimate of the odds ratio (OR) and the red lines represent the 95% CI. Possible “hitchhiking” effects from nonsynonymous sites are reduced by discarding any TASP/control SNP in r2 > 0.6 with a nonsynonymous SNP. For an explanation of the annotation sets on the x axis, we refer the reader to Table S4. Note that the y axis is on the log scale. Nonsynonymous OR computation is not adjusted for “hitchhiking” effects.