Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.
Chen, L; Ge, B; Casale, FP; Vasquez, L; Kwan, T; Garrido-Martín, D; Watt, S; Yan, Y; Kundu, K; Ecker, S; Datta, A; Richardson, D; Burden, F; Mead, D; Mann, AL; Fernandez, JM; Rowlston, S; Wilder, SP; Farrow, S; Shao, X; Lambourne, JJ; Redensek, A; Albers, CA; Amstislavskiy, V; Ashford, S; Berentsen, K; Bomba, L; Bourque, G; Bujold, D; Busche, S; Caron, M; Chen, S-H; Cheung, W; Delaneau, O; Dermitzakis, ET; Elding, H; Colgiu, I; Bagger, FO; Flicek, P; Habibi, E; Iotchkova, V; Janssen-Megens, E; Kim, B; Lehrach, H; Lowy, E; Mandoli, A; Matarese, F; Maurano, MT; Morris, JA; Pancaldi, V; Pourfarzad, F; Rehnstrom, K; Rendon, A; Risch, T; Sharifi, N; Simon, M-M; Sultan, M; Valencia, A; Walter, K; Wang, S-Y; Frontini, M; Antonarakis, SE; Clarke, L; Yaspo, M-L; Beck, S; Guigo, R; Rico, D; Martens, JHA; Ouwehand, WH; Kuijpers, TW; Paul, DS; Stunnenberg, HG; Stegle, O; Downes, K; Pastinen, T; Soranzo, N
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