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Effect of All-but-One Conditional Analysis for eQTL Isolation in Peripheral Blood.

Expression quantitative trait locus (eQTL) detection has become increasingly important for understanding how non-coding variants contribute to disease susceptibility and complex traits. The major challenges in eQTL fine-mapping and causal variant discovery relate to the impact of linkage disequilibrium on signals due to one or multiple functional variants that lie within a credible set. We perform eQTL fine-mapping using the all-but-one approach, conditioning each signal on all others detected in an interval, on the CAGE cohorts of microarray-based peripheral blood gene expression in 2,138 European-ancestry human adults. We contrast these results with traditional forward stepwise conditional analysis and a Bayesian localization method. All-but-one conditioning significantly modifies effect-size estimates for 51% of 2,351 eQTL peaks, but only modestly affects credible set size and location. On the other hand, both conditioning approaches result in unexpectedly low overlap with Bayesian credible sets, with just 57% peak concordance and between 50% and 70% SNP sharing, leading us to caution against the assumption that any one localization method is superior to another. We also cross reference our results with ATAC-seq data, cell-type specific eQTL, and ABC-enhancers, leading to the proposal of a 5-tier approach to further reduce credible set sizes and prioritize likely causal variants for all known inflammatory bowel disease risk loci active in immune cells.