2023 Theses Doctoral

Genotype-Phenotype Correlation of T Cells from Aged and Alzheimer's Disease Subjects

Dressman, Dallin

Alzheimer’s disease (AD) affects tens of millions of people worldwide. Its cause is unknown, with no cure, and disease-modifying treatment options have only recently become available. Emerging research has made a strong case for the involvement of immune cells, such as microglia and T cells, in modulating AD pathology. Newer technologies in RNA-sequencing have detailed specific phenotypic changes to microglia and T cells over the course of neurodegenerative disease. Some researchers have also used whole-genome sequencing to correlate genetic variants with changes in gene expression. However, no studies thus far have conducted this type of genotype-phenotype correlation in immune cells from aged individuals or AD patients.

We have collected gene expression data from four sorted T cell subtypes in peripheral blood samples from 96 subjects in ROSMAP, a cohort of AD patients and age-matched controls. 78 of these subjects also have whole-genome sequencing data, which we used to detect genetic variants associated with changes in T cell gene expression. These are known as expression quantitative trait loci (eQTL). We found genes related to T cell cytotoxicity and immunosenescence in gene co-expression modules, among the eQTL, and in correlation with AD neuropathological traits or risk variants for several disease traits. We extended our findings related to disease association by calculating polygenic risk scores (PRSs) in our cohort from whole-genome sequencing data for 19 traits related to immune function and disease, including AD. Genes associated with the PRS for one or more disease traits often were in biological pathways related to downstream cytokine signaling, regulation of T cell receptor signaling, and T cell migration and trafficking.

Overall, our findings indicate that the use of aged and AD patients in T cell genotype-phenotype correlation studies highlights genetic variants and differentially expressed genes that are not seen in studies using young, healthy individuals.