The Genetic Architecture of the Human Immune System: Building Bridges to Mechanisms of Autoimmunity and Immunopathogenesis

The human body carefully regulates the number cells in the blood. For example, in healthy adults CD4:CD8 ratio is approximately 2:1; within CD4 T cells, the naïve:memory ratio is typically 1:1. Mechanisms that regulate these balances are poorly, if it all, known. Furthermore, disregulation in the homeostasis of these cells often accompanies or leads to disease. We hypothesized that insight into homeostasis mechanisms could be revealed by quantifying the heritability of the representation of leukocyte subsets in healthy related adults, and performing GWAS to identify the associated genetic loci. We developed seven 14-color immunophenotyping panels to quantify a broad range of leukocytes in PBMC from 668 healthy twins. Over 78,000 gates (subset representation) and nearly 700 MFI values (subset phenotype) were computed. Standard twin based heritability analysis was used to identify the top 150 independent traits, which were subjected to GWAS analysis. We identified 297 SNP associations at 11 genetic loci that explain up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets, and uncovered insights into the genetic control for regulatory T cells. Importantly, the data also revealed immune traits associated with loci known to confer autoimmune susceptibility, providing novel mechanistic hypotheses that link the traits to the etiology of diseases. Our data link genetic control elements associated with immune traits to autoimmune susceptibility, providing a shortcut to identify mechanisms

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