Integrative approaches to prioritize and characterize Alzheimer’s disease genes identify gene targets that may protect against Alzheimer’s

FunGen-AD investigators from Baylor College of Medicine led by Juan Botas including Morgan Stephens, Ismael Al-Ramahi, and Joshua Shulman integrated Alzheimer’s disease (AD) genome-wide association studies (GWAS) data with multiple computational approaches to identify genes that were more likely involved in AD.

The group nominated potential AD risk genes based on transcriptome-wide association study (TWAS) analyses. These genes were then computationally assessed using several orthogonal methods, including colocalization analysis, fine-mapping, and annotation of AD GWAS variants. These assessments identified 123 genes at known and suggestive AD risk loci. Further analysis confirmed that the expression of many of these genes was altered in human AD cases and correlated with tau or amyloid-beta (Aβ) accumulation in AD brains. The researchers then evaluated 60 of these gene candidates in tau and Aβ42 Drosophila models using a locomotor behavior assay to quantitatively assess neuronal dysfunction as the animals aged. These experiments showed that 46 of the gene candidates modulated neuronal dysfunction in one or both AD fly models. Notably, altered expression of 18 of these genes predicted increased AD risk in humans based on TWAS analyses and exacerbated motor impairments in the AD fly models. Reversing the up- or downregulation of 11 of these genes provided protection against neuronal dysfunction in the AD fly models.

Further study of one of these 11 genes, MTCH2, found that its expression is downregulated in human AD brain samples. Reducing MTCH2 expression in AD flies further exacerbated behavioral impairments; increasing MTCH2 expression in these flies reversed this dysfunction. Additionally, boosting MTCH2 expression in both flies and human neuronal progenitor cells reduced tau accumulation. These results point to MTCH2 as a potential therapeutic target. Overall, this study demonstrate that an integrative computational and experimental approach can effectively prioritize genes identified by GWAS and support further investigations of therapeutic targets for AD.

This research, partially supported by FunGen-AD grant U01AG072439, is published in The American Journal of Human Genetics here. You can read more about these research findings at the following links: