Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression.
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We thank the ImmVar participants. We would like to thank J. Buenrostro for critical reading of the manuscript and advice on ATAC-seq analysis, J. Pfiffner and C. Fulco for initial experimental help with ATAC-seq, A. Schep for ATAC-seq nucleosome free caller, N. Asinovski and H.-k. Kwon for help setting up primary T cell cultures and members of the Regev and Ye laboratories for discussions. R.E.G. and C.J.Y. are supported by NIH R01-AR071522 to C.J.Y. M.A.B. and K.L.H. are supported by NIH HG007348 to M.A.B.; H.Y.C. is supported by NIH grant P50-HG007735; C.S.C. is supported by the NIH through a Ruth L. Kirschstein National Research Service Award (F32-DK096822). This work was supported by the Klarman Cell Observatory at the Broad Institute. A.R. is a Howard Hughes Medical Institute Investigator.
A.R. is an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals and Driver group and a founder of Celsius Therapeutics.
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PC correlation to chromatin accessibility and gene expression
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Gate, R.E., Cheng, C.S., Aiden, A.P. et al. Genetic determinants of co-accessible chromatin regions in activated T cells across humans. Nat Genet 50, 1140–1150 (2018). https://doi.org/10.1038/s41588-018-0156-2
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