Combining cell type-specific genomic/epigenomic analyses and experimental validation identifies genetic drivers across three neurodegenerative diseases

The genetic underpinnings of neurodegenerative disease risk remain poorly characterized due to the lack of a unified framework for synthesizing causal evidence from diverse statistical and biological sources. Here, we present an integrative approach to analyze Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) risk that unifies evidence from Mendelian randomization, colocalization, cell type-specific genomic and epigenomic profiling, human induced pluripotent stem cell (iPSC) and mouse model-based functional validation. We identified 173 high confidence risk genes: 105 for AD, 50 for PD, and 27 for ALS. Single-nucleus multi-omics revealed distinct cell type-specific regulatory architectures, with AD risk genes enriched in microglia and PD and ALS risk genes predominantly associated with neurons and oligodendrocytes. Functional mechanisms were elucidated for specific variants, including a non-coding variant (rs1171832) that regulates expression of the DNA repair and cell cycle CCDC6 gene by modulating chromatin accessibility in microglia and we further validate it in human iPSC derived microglia by CRISPRi experiments. A nonsynonymous mutation (p.P290A) in the mitochondrial metabolism gene MTCH2 (rs1064608) that increases its neuronal expression and elevates AD risk. We found that AAV-mediated delivery of mutated MTCH2 gene ameliorated cognitive deficits in a mouse model, indicating a protective role. This work establishes a functional genomic framework that bridges genetic association with molecular mechanism and target validation, uncovering cell type-specific genetic drivers of neurodegenerative diseases.