A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci

Abstract

We conducted a comprehensive study of copy number variants (CNVs) well-tagged by SNPs (r(2)≥ 0.8) by analyzing their effect on gene expression and their association with disease susceptibility and other complex human traits. We tested whether these CNVs were more likely to be functional than frequency-matched SNPs as trait-associated loci or as expression quantitative trait loci (eQTLs) influencing phenotype by altering gene regulation. Our study found that CNV-tagging SNPs are significantly enriched for cis eQTLs; furthermore, we observed that trait associations from the NHGRI catalog show an overrepresentation of SNPs tagging CNVs relative to frequency-matched SNPs. We found that these SNPs tagging CNVs are more likely to affect multiple expression traits than frequency-matched variants. Given these findings on the functional relevance of CNVs, we created an online resource of expression-associated CNVs (eCNVs) using the most comprehensive population-based map of CNVs to inform future studies of complex traits. Although previous studies of common CNVs that can be typed on existing platforms and/or interrogated by SNPs in genome-wide association studies concluded that such CNVs appear unlikely to have a major role in the genetic basis of several complex diseases examined, our findings indicate that it would be premature to dismiss the possibility that even common CNVs may contribute to complex phenotypes and at least some common diseases.

Figure 1. SNPs tagging tCNVs are likely to be eQTLs.

(A) SNPs tagging tCNVs (r²≥0.80) are enriched for cis-acting eQTLs (eQTLs within 4 mb of target transcript). The distribution of the number of cis-acting eQTLs (at p<10⁻⁴) in 1,000 draws (each of same count as the number of tCNVs) of frequency-matched variants is shown in the bar graphs, with the actual number of cis-acting eQTLs observed in the tCNVs from the Wellcome Trust study shown as a solid circle. (B) SNPs tagging tCNVs are more likely to be eQTLs that predict the transcript levels of 10 or more genes than frequency-matched variants.

Figure 2. Trait-associated SNPs are significantly enriched for SNPs tagging tCNVs.

The distribution of the number of SNPs tagging tCNVs in 1,000 draws of SNPs from bins matched for minor allele frequency to the trait-associated SNPs is shown in the bar graphs.