Leveraging Molecular Quantitative Trait Loci to Understand the Genetic Architecture of Diseases and Complex Traits

Overview

Journal Nat Genet

Specialty Genetics

Date 2018 Jun 27

PMID 29942083

Citations 98

Authors

Farhad Hormozdiari

Steven Gazal

Bryce van de Geijn

Hilary K Finucane

Chelsea J-T Ju

Po-Ru Loh

Armin Schoech

Yakir Reshef

Xuanyao Liu

Luke OConnor

Alexander Gusev

Eleazar Eskin

Alkes L Price

Affiliations

Soon will be listed here.

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.

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