candidate causal regulatory effects by integration of expression qtls with complex trait genetic associations候选人因果一体化监管效果的表达法具有复杂性状的遗传关联.pdfVIP

Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations Alexandra C. Nica1,2, Stephen B. Montgomery1,2, Antigone S. Dimas1,2, Barbara E. Stranger1,3, Claude 1 ˆ 1 1,2 Beazley , Ines Barroso , Emmanouil T. Dermitzakis * 1 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom, 2 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, 3 Harvard Medical School/Brigham and Women’s Hospital, Boston, Massachusetts, United States of America Abstract The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases. Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants. In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r2) or historical (D’). Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex