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Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types

Abstract

Most autoimmune-disease-risk effects identified by genome-wide association studies (GWAS) localize to open chromatin with gene-regulatory activity. GWAS loci are also enriched in expression quantitative trait loci (eQTLs), thus suggesting that most risk variants alter gene expression1,2. However, because causal variants are difficult to identify, and cis-eQTLs occur frequently, it remains challenging to identify specific instances of disease-relevant changes to gene regulation. Here, we used a novel joint likelihood framework with higher resolution than that of previous methods to identify loci where autoimmune-disease risk and an eQTL are driven by a single shared genetic effect. Using eQTLs from three major immune subpopulations, we found shared effects in only 25% of the loci examined. Thus, we show that a fraction of gene-regulatory changes suggest strong mechanistic hypotheses for disease risk, but we conclude that most risk mechanisms are not likely to involve changes in basal gene expression.

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Figure 1: Only a minority of disease associations share genetic effects with eQTLs across three immune-cell subpopulations.
Figure 2: A multiple sclerosis association on chromosome 12 is consistent with eQTLs for METTL21B in both CD4+ T cells and CD14+ monocytes.
Figure 3: Associations with multiple sclerosis (MS), Crohn disease and rheumatoid arthritis (RA) on chromosome 5 are consistent with an eQTL for ANKRD55 in CD4+ T cells.

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Acknowledgements

S.R.S. and S.C. were supported by NIH awards R01-MH101244-04, R01-GM105857-03, R01-GM078598-09 and U01-HG009088-01.

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S.C. designed and performed research and authored the manuscript; A.C. performed research; N.A.P., D.C.C.-C., B.A.R. and P.L.D.J. contributed data and approved the manuscript; S.R.S. and C.C. designed and performed research and authored the manuscript.

Corresponding authors

Correspondence to Shamil R Sunyaev or Chris Cotsapas.

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The authors declare no competing financial interests.

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Supplementary Figures 1–27, Supplementary Tables 1–4 and Supplementary Note (PDF 9597 kb)

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Chun, S., Casparino, A., Patsopoulos, N. et al. Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types. Nat Genet 49, 600–605 (2017). https://doi.org/10.1038/ng.3795

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