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Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites, while schizophrenia heritability is predominantly enriched at chromatin contact sites in neurons followed by oligodendrocytes. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA), we identified disease risk genes for Alzheimer\u2019s disease, Parkinson\u2019s disease, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions and within neurons for schizophrenia. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011407","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T13:39:38Z","timestamp":1744205978000},"page":"e1011407","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways"],"prefix":"10.1371","volume":"21","author":[{"given":"Aydan","family":"Askarova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4565-5903","authenticated-orcid":true,"given":"Reuben M.","family":"Yaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Marzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2029-7193","authenticated-orcid":true,"given":"Alexi","family":"Nott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"issue":"3","key":"pgen.1011407.ref001","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1212\/WNL.5.3.182","article-title":"Epidemiologic investigations of amyotrophic lateral sclerosis. 2. 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