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Hormozdiari, Farhad; Gazal, Steven; van de Geijn, Bryce; Finucane, Hilary K; Ju, Chelsea J-T; Loh, Po-Ru; Schoech, Armin; Reshef, Yakir; Liu, Xuanyao; O'Connor, Luke; Gusev, Alexander; Eskin, Eleazar; Price, Alkes L
Nature genetics, 07/2018, Letnik: 50, Številka: 7Journal Article
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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