Genetic determinants of co-accessible chromatin regions in activated T cells across humans.
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Abstract | 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. |
Year of Publication | 2018
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Journal | Nat Genet
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Volume | 50
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Issue | 8
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Pages | 1140-1150
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Date Published | 2018 08
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ISSN | 1546-1718
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DOI | 10.1038/s41588-018-0156-2
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PubMed ID | 29988122
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PubMed Central ID | PMC6097927
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Grant list | F32 DK096822 / DK / NIDDK NIH HHS / United States
R21 AI133337 / AI / NIAID NIH HHS / United States
F32 CA168253 / CA / NCI NIH HHS / United States
U01 HG009380 / HG / NHGRI NIH HHS / United States
RM1 HG006193 / HG / NHGRI NIH HHS / United States
R01 HG007348 / HG / NHGRI NIH HHS / United States
R01 AR071522 / AR / NIAMS NIH HHS / United States
P50 HG007735 / HG / NHGRI NIH HHS / United States
T32 GM067547 / GM / NIGMS NIH HHS / United States
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