How to interpret the biological causes underlying the predisposing markers identified through genome-wide association studies (GWAS) remains an open question. One direct and powerful way to assess the genetic causality behind GWAS is through analysis of expression quantitative trait loci (eQTLs). Here we describe a new approach to estimate the tissues behind the genetic causality of a variety of GWAS traits, using the cis-eQTLs in 44 tissues from the Genotype-Tissue Expression (GTEx) Consortium. We have adapted the regulatory trait concordance (RTC) score to measure the probability of eQTLs being active in multiple tissues and to calculate the probability that a GWAS-associated variant and an eQTL tag the same functional effect. By normalizing the GWAS–eQTL probabilities by the tissue-sharing estimates for eQTLs, we generate relative tissue-causality profiles for GWAS traits. Our approach not only implicates the gene likely mediating individual GWAS signals, but also highlights tissues where the genetic causality for an individual trait is likely manifested.
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This research was supported by grants from the US National Institutes of Health (NIH-R01MH101814), European Commission Framework Programme 7 (UE7-SYSCOL-258236), the European Research Council (UE7-POPRNASEQ-260927), the Swiss National Science Foundation (31003A-149984 and 31003A-170096), and the Louis Jeantet Foundation. Computations were performed at the Vital-IT Centre for High-Performance Computing of the SIB Swiss Institute of Bioinformatics.
The authors declare no competing financial interests.
A list of members and affiliations appears in the Supplementary Note.
Supplementary Figures 1–19 and Supplementary Note (PDF 1417 kb)
Mean eQTL tissue sharing probabilities across 44 tissues. (XLSX 35 kb)
Proportions of the number of tissues an eQTL (FDR = 5%) is active in, for the 44 GTEx tissues. (XLSX 31 kb)
Frequency of tissues being included in the most likely set of tissues for all eQTLs discovered. (XLSX 33 kb)
Various error statistics for r2. (XLSX 17 kb)
Enrichment over the null for the GWAS traits. (XLSX 315 kb)
Nominal P values for enrichments over the null for the GWAS traits. (XLSX 261 kb)
Normalized tissue causality profile for the GWAS traits. (XLSX 333 kb)
GWAS–eQTL probabilities. (XLSX 1923 kb)
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Ongen, H., Brown, A., Delaneau, O. et al. Estimating the causal tissues for complex traits and diseases. Nat Genet 49, 1676–1683 (2017). https://doi.org/10.1038/ng.3981
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