Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

TLDR

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. The study quantitatively assesses how cis‑genetic and epigenetic factors influence transcription and their potential to confound epigenome‑wide association studies. High‑resolution genetic, epigenetic, and transcriptomic profiling of CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells from up to 197 individuals was combined with QTL mapping and allele‑specific analyses to quantify these contributions. The authors found colocalization of molecular trait QTLs at 345 immune disease loci and produced a high‑resolution atlas that reveals cell‑type‑specific and generalizable correlations among genetic, epigenetic, and transcriptional inputs, highlighting molecular events that may underpin complex disease risk.

Abstract

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.