Bayesian Test for Colocalisation Between Pairs of Genetic Association Studies Using Summary Statistics

Genetic association studies, in particular the genome-wide association study design, have provided a wealth of novel insights into the aetiology of a wide range of human diseases and traits. The next challenge consists of understanding the molecular basis of these associations. The integration of multiple association datasets, including gene expression datasets, can contribute to this goal. We have developed a novel statistical methodology to assess whether two association signals are consistent with a shared causal variant. An application is the integration of disease scans with expression quantitative trait locus (eQTL) studies, but any pair of GWAS datasets can be integrated in this framework. We demonstrate the value of the approach by reanalysing a gene expression dataset in 966 liver samples with a published meta-analysis of lipid traits including >100, 000 individuals of European ancestry. Combining all lipid biomarkers, our reanalysis supported 29 out of 38 reported colocalisation results with eQTLs and identified 14 new colocalisation results, highlighting the value of a formal statistical test. In two cases of reported eQTL-lipid pairs (IFT172, TBKBP1) for which our analysis suggests that the eQTL pattern is not consistent with the lipid association, we identify alternative colocalisation results with GCKR and KPNB1, indicating that these genes are more likely to be causal in these genomic intervals. A key feature of the method is the ability to derive the output statistics from single SNP summary statistics, hence making it possible to perform systematic meta-analysis type comparisons across multiple GWAS datasets (http://coloc.cs.ucl.ac.uk/coloc/). Our methodology provides information about candidate causal genes in associated intervals and has direct implications for the understanding of complex diseases and the design of drugs to target disease pathways.