Tu57 - Genotype-Phenotype Correlation of T cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer’s Disease

Following the discovery of several key risk variants for Alzheimer’s disease (AD) in genes related to immune function, much has been done to catalogue the genetic landscape and transcriptomic profiles of microglia and T cells in health and disease.  Several recent studies investigate expression quantitative trait loci (eQTL), which correlate risk variants with gene expression changes, in T cells.  However, these studies primarily involve healthy young donors, which may preclude detection of age- or disease-related phenotypic changes.  We have collected whole-genome and RNA sequencing data to detect eQTL in four T cell subsets from 96 participants in the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort of aged and AD subjects.  Gene co-expression modules reveal several genes related to IL-10 signaling in one module, and genes related to cytotoxicity and immunosenescence in another.  We also compared single nucleotide polymorphisms (SNPs) from the trans-eQTL to disease-associated SNPs from the GWAS catalog database.  We discovered that several dozen SNPs among the four T cell subsets matched GWAS catalog SNPs previously correlated with traits related to immune function, neurodegenerative disease, autoimmune disease, and psychiatric disorders.  Running pathway analysis on genes that included SNPs from the trans-eQTL between their transcription start site and end site returned top biological pathways related to synaptic function, axon guidance, and nerve cell development, suggesting that neurodevelopmental processes could regulate adaptive immune responses.  We are currently investigating key genes and variants in cell culture and mouse models to lend mechanistic relevance to our findings and identify additional therapeutic targets.