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

Seyhan YazarJose Alquicira HernandezKristof WingAnne SenabouthM Grace GordonStacey AndersenQinyi LuAntonia RowsonThomas R P TaylorLinda ClarkeKatia MaccoraChristine ChenAnthony L CookChun Jimmie YeKirsten A FairfaxAlex W HewittJoseph E Powell
Published in: Science (New York, N.Y.) (2022)
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.
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