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Nat Genet DOI:10.1038/s41588-018-0148-2

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

Publication TypeJournal Article
Year of Publication2018
AuthorsHormozdiari, 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
JournalNat Genet
Date Published2018 07
KeywordsDisease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable

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.


Alternate JournalNat Genet
PubMed ID29942083
PubMed Central IDPMC6030458
Grant ListR01 MH101782 / MH / NIMH NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
T32 DK110919 / DK / NIDDK NIH HHS / United States
U01 HG009379 / HG / NHGRI NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
R01 MH109978 / MH / NIMH NIH HHS / United States
F32 HG009987 / HG / NHGRI NIH HHS / United States
R01 MH107649 / MH / NIMH NIH HHS / United States