Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease

TLDR

The human immune system varies substantially between individuals, influencing susceptibility to autoimmune disease. This work integrates genetic epidemiology with single‑cell RNA sequencing to uncover drivers of interindividual immune variation. The authors generated scRNA‑seq data from 1,267,758 peripheral blood mononuclear cells across 982 healthy donors. They identified 26,597 cis‑ and 990 trans‑eQTLs in 14 cell types—most cell‑type specific—demonstrated dynamic allelic effects during B‑cell maturation, and used Mendelian randomization to link 305 autoimmune risk loci to cellular disease mechanisms.

Abstract

The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type-specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interindividual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interindividual variation in the immune system.