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

Combining cell type-specific genomic/epigenomic analyses and experimental validation identifies genetic drivers across three neurodegenerative diseases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Combining cell type-specific genomic/epigenomic analyses and experimental validation identifies genetic drivers across three neurodegenerative diseases Yuan Hou, Liam Wetzel, Xin Chen, Xiaoyu Yang, Dina Bugybayeva, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8779983/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 12 You are reading this latest preprint version Abstract 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. Full Text Additional Declarations Competing interest reported. Dr. Cummings has provided consultation to AB Science, Acadia, Alkahest, AlphaCognition, ALZPathFinder, Annovis, AriBio, Artery, Avanir, Biogen, Biosplice, Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PharmacotrophiX, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, Unlearn AI, Vaxxinity, VigilNeuro pharmaceutical, assessment, and investment companies. The other authors have declared no competing interests. Supplementary Files SupplementaryFiguresS1S8Cheng.pdf SupplementaryTablesS1S9.zip westernblotdata.zip Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 30 Apr, 2026 Reviews received at journal 30 Apr, 2026 Reviews received at journal 20 Apr, 2026 Reviews received at journal 18 Apr, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 09 Apr, 2026 Reviewers agreed at journal 26 Feb, 2026 Reviewers invited by journal 26 Feb, 2026 Editor assigned by journal 19 Feb, 2026 Submission checks completed at journal 11 Feb, 2026 First submitted to journal 03 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8779983","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597670956,"identity":"ba8be414-073d-4be3-9522-14b70395cb60","order_by":0,"name":"Yuan Hou","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Hou","suffix":""},{"id":597670957,"identity":"c8e64471-4904-436f-a2e9-04054cf0d566","order_by":1,"name":"Liam Wetzel","email":"","orcid":"","institution":"Case Western Reserve 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Dr. Cummings has provided consultation to AB Science, Acadia, Alkahest, AlphaCognition, ALZPathFinder, Annovis, AriBio, Artery, Avanir, Biogen, Biosplice, Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PharmacotrophiX, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, Unlearn AI, Vaxxinity, VigilNeuro pharmaceutical, assessment, and investment companies. 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Here, we present an integrative approach to analyze Alzheimer\u0026rsquo;s disease (AD), Parkinson\u0026rsquo;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 \u003cem\u003eCCDC6\u003c/em\u003e 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 \u003cem\u003eMTCH2\u003c/em\u003e (rs1064608) that increases its neuronal expression and elevates AD risk. We found that AAV-mediated delivery of mutated \u003cem\u003eMTCH2\u003c/em\u003e 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.\u003c/p\u003e","manuscriptTitle":"Combining cell type-specific genomic/epigenomic analyses and experimental validation identifies genetic drivers across three neurodegenerative diseases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-03 15:09:49","doi":"10.21203/rs.3.rs-8779983/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-30T19:18:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T18:57:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T15:35:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-19T03:29:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209239554574234866345787570844074597848","date":"2026-04-17T13:41:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"201190644927911686253850648405717508715","date":"2026-04-15T14:44:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139046664396517041926118474368025496148","date":"2026-04-09T15:01:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225010458960282904679821600210010250501","date":"2026-02-26T15:57:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-26T15:37:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-19T21:29:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-11T06:15:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Neurodegeneration","date":"2026-02-03T21:32:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-neurodegeneration","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mond","sideBox":"Learn more about [Molecular Neurodegeneration](http://molecularneurodegeneration.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mond/default.aspx","title":"Molecular Neurodegeneration","twitterHandle":"@MolNeuro","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ad3f5c77-38bb-4bc9-b568-2566c61f1bf3","owner":[],"postedDate":"March 3rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-04-30T19:18:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T18:57:02+00:00","index":33,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T19:24:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-03 15:09:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8779983","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8779983","identity":"rs-8779983","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}