Document Type
Article
Publication Date
1-1-2026
Original Citation
Kaur S,
Tyler AL,
Durante G,
Cary G,
Carter GW,
Mahoney J.
Identifying transcriptomic signatures that mediate the causal effect of genotype on Alzheimer's disease. Front Neurosci. 2026;20:1716828.
Keywords
JMG
JAX Source
Front Neurosci. 2026;20:1716828.
ISSN
1662-4548
PMID
41938695
DOI
https://doi.org/10.3389/fnins.2026.1716828
Grant
This work was supported by the National Science Foundation (award 2244034), NIH grant R01GM141309, the Emory-Sage-SGC-JAX TREAT-AD Center, and the National Institute on Aging grant U54AG065187. Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG36836 (RNAseq), P30AG072975, the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic).
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, the set of all gene expression levels for every gene in the genome, is a major mediator between the genotype to phenotype. This study uses genotypes, transcriptomes, and clinical phenotypes to identify the transcriptomic signature that mediates the causal effect of genotype on AD. By utilizing a causal inference method known as high dimensional mediation analysis (HDMA) on the Religious Orders Study/Memory and Aging Project (ROSMAP) longitudinal cohort, the genotype, transcriptome, and phenotype data were reduced to single scores encoding genotype, transcriptome, and phenotype correlations, and produce a ranked gene list based on putative causal importance of each gene for AD. Analysis of the up- and down-regulated genes prevalent in AD through Gene Ontology (GO) and KEGG databases reveals findings such as up-regulated functions which include angiogenesis and immune responses while down-regulated functions of genes include synaptic activity. Furthermore, utilizing Clue.io to identify candidate drugs to suppress AD-pathology reveals a plausible list of therapeutic candidates, including targeted genes and compounds such as SMAD3, TM7SF2, and ABCB1, which counteract the transcriptomic signature identified and may block the devastating effects of AD related to inflammatory responses, Aβ-induced toxicity, and neuronal death.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.