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

Nat Genet. 2018 Jul;50(7):1041-1047. doi: 10.1038/s41588-018-0148-2. Epub 2018 Jun 25.

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 × 10-31) 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 × 10-35). 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Disease / genetics*
  • Genome-Wide Association Study / methods
  • Humans
  • Multifactorial Inheritance*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Quantitative Trait, Heritable