Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators

Abstract

Summary: The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%–20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives. : Lagou et al. identify genetic factors explaining interindividual variation in composition of the adaptive immune system. Factors pinpoint key human immune regulators controlling B and T cell differentiation and levels of disease-relevant T helper and regulatory cells. These findings shed light on mechanisms of autoimmune disease and offer therapeutic perspectives. Keywords: adaptive immune system, immune phenotype, genetics, association, genome-wide association, autoimmunity, susceptibility