Leveraging molecular quantitative trait loci to understand the genetic architecture of diseases and complex traits

Citation:

Hormozdiari F, Gazal S, van de Geijn B, Finucane HK, Ju CJ-T, Loh P-R, Schoech A, Reshef Y, Liu X, O'Connor L, Gusev A, Eskin E, Price AL. Leveraging molecular quantitative trait loci to understand the genetic architecture of diseases and complex traits. Nat Genet 2018;50(7):1041-1047.

Date Published:

2018 Jul

Abstract:

There is increasing evidence that many risk loci found using genome-wide association studies are molecular quantitative trait loci (QTLs). Here we introduce a new set of functional annotations based on causal posterior probabilities of fine-mapped molecular cis-QTLs, using data from the Genotype-Tissue Expression (GTEx) and BLUEPRINT consortia. We show that these annotations are more strongly enriched for heritability (5.84× for eQTLs; P = 1.19 × 10) across 41 diseases and complex traits than annotations containing all significant molecular QTLs (1.80× for expression (e)QTLs). eQTL annotations obtained by meta-analyzing all GTEx tissues generally performed best, whereas tissue-specific eQTL annotations produced stronger enrichments for blood- and brain-related diseases and traits. eQTL annotations restricted to loss-of-function intolerant genes were even more enriched for heritability (17.06×; P = 1.20 × 10). All molecular QTLs except splicing QTLs remained significantly enriched in joint analysis, indicating that each of these annotations is uniquely informative for disease and complex trait architectures.

Last updated on 07/11/2018