Identifying Transcriptomic Signatures to Mediate Causal Effect of Genotype on Alzheimer's Disease

Simran Kaur

Document Type

Article

Publication Date

Summer 2023

Keywords

JMG

JAX Location

In: Student Reports, Summer 2023, The Jackson Laboratory

Abstract

The combined effects of thousands of genetic polymorphisms account for Alzheimer’s disease (AD) genetic risk. Most AD polymorphisms affect gene expression. Thus, the transcriptome, i.e., the set of all gene expression levels for every gene in the genome, is the major mediator between the genotype to phenotype. The purpose of this project is to use genotypes, transcriptomes, and clinical phenotypes to identify the transcriptomic signature that mediates the causal effect of genotype on AD. By utilizing high dimensional mediation analysis (HDMA) and the ROSMAP longitudinal cohort, we reduce the genotype, transcriptome, and phenotype data to single scores encoding genotype, transcriptome, and phenotype correlations, and produce a ranked gene list based on causal importance of each gene for AD. Analysis of the up- and down-regulated genes prevalent in AD through Gene Ontology and KEGG databases reveals up-regulated functions which include angiogenesis and immune responses while down-regulated functions of genes include synaptic activity. Utilizing Clue.io to identify candidate drugs to suppress AD-pathology reveals a plausible list of therapeutic candidates, including compounds targeting genes such as ZNF384, TYK2, and AZD-5438, which counteract the transcriptomic signature we identified and may block the devastating effects of AD related to the inflammatory responses, Aβ-induced cell death, and neuronal death.

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