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

• Published in: Science (American Association for the Advancement of Science) Vol. 376; no. 6589; p. eabf3041
• Main Authors: Yazar, Seyhan, Alquicira-Hernandez, Jose, Wing, Kristof, Senabouth, Anne, Gordon, M Grace, Andersen, Stacey, Lu, Qinyi, Rowson, Antonia, Taylor, Thomas R P, Clarke, Linda, Maccora, Katia, Chen, Christine, Cook, Anthony L, Ye, Chun Jimmie, Fairfax, Kirsten A, Hewitt, Alex W, Powell, Joseph E
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 08-04-2022
• Subjects: Alleles; Autoimmune diseases; Autoimmune Diseases - genetics; Cancer; Cell differentiation; Chromosome 3; Chronic conditions; Disease; Disease control; Gene expression; Gene Expression Regulation; Gene mapping; Gene polymorphism; Gene sequencing; Genes; Genetic control; Genetic diversity; Genetic effects; Genetic Predisposition to Disease; Genetic variance; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Homeostasis; Humans; Immune response; Immune system; Leukocytes, Mononuclear; Lymphocytes B; Major histocompatibility complex; Memory cells; Multiple sclerosis; Nucleotides; Pathogens; Peripheral blood mononuclear cells; Polymorphism; Polymorphism, Single Nucleotide; Population genetics; Population studies; Populations; Precursor Cells, B-Lymphoid; Quantitative Trait Loci; Ribonucleic acid; RNA; Sequence Analysis, RNA; Statistical analysis; Transplantation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abf3041

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.