Genome-wide association meta-analysis of Alzheimer's disease in Colombian, Argentinian, and Chilean populations

Genome-wide association meta-analysis of Alzheimer's disease in Colombian, Argentinian, and Chilean populations | 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 Article Genome-wide association meta-analysis of Alzheimer's disease in Colombian, Argentinian, and Chilean populations Alfredo Ramirez, Carlos Arboleda-Bustos, Gonzalo Arboleda, Rodrigo Pardo, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8996305/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Latin American populations are underrepresented in Alzheimer’s disease (AD) genome-wide association studies (GWAS), limiting ancestry-specific risk prediction. To address this gap, a GWAS was conducted with 254 AD cases and 241 controls from Colombia, followed by a trans-ancestry meta-analysis that incorporated cohorts from Colombia, Chile, Argentina, and the European EADB consortium. AD polygenic risk scores (AD-PRS) derived from the Latin American GWAS were compared with those from European GWAS. APOE -ε4 showed the strongest association in Colombians (OR=3.33, P =1.81×10 -9 ). The meta-analysis identified five loci, including a population-specific signal at FBXO33/MIA2 (OR=1.09, P =8.39×10 -9 ). Additionally, a missense coding variant at GCAT , first identified in a Caribbean Hispanic cohort with enriched Native American ancestry (NAM), was validated in our admixed population with strong NAM ancestry (OR=2.55, P =1.00×10 -4 ). The accuracy of European-derived AD-PRSs was largely driven by APOE and declined with increasing NAM, whereas Latin American-derived AD-PRS captured ancestry-specific polygenic risk beyond APOE adjustment. These findings indicate that AD risk in Colombians reflects both shared and ancestry-specific genetic effects. In addition, our results suggest that genetic datasets from admixed Latin American populations are beginning to reach the scale and resolution necessary not only to replicate established AD loci but also to identify population-specific variants, including novel signals and refined associations at previously implicated loci. These results underscore the importance of ancestry-matched GWAS and PRS development to achieve equitable and biologically accurate AD risk prediction. Biological sciences/Genetics Biological sciences/Neuroscience Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files SupplementaryFigure1.docx Manhattan Plot displaying the meta-analysis of Colombian, Argentinian and Chilean samples. SupplementaryFigure2.docx Regional association plots for three loci that gain significance with the inclusion of Colombian samples. SupplementaryFigure3.docx Polygenic risk score (PRS) model fit (R²) across multiple P -value thresholds (PT) in the Colombian cohort. SupplementaryFigure4.docx Linear regression model (LRM) showing the relationship between PRS and Native American (NAM) ancestry, based on 73 EADB genome-wide significant SNPs reported in Bellenguez et al. 2022. SupplementaryTables.xlsx Supplementary tables Cite Share Download PDF Status: Under Review Version 1 posted Reviewer # 1 agreed at journal 28 Apr, 2026 Reviewers invited by journal 28 Apr, 2026 Editor assigned by journal 03 Mar, 2026 Submission checks completed at journal 03 Mar, 2026 First submitted to journal 02 Mar, 2026 Unknown event 02 Mar, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8996305","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":600142413,"identity":"29f6f0c9-cbfd-43c3-aab2-989eac976274","order_by":0,"name":"Alfredo 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Argentinian and Chilean samples.","description":"","filename":"SupplementaryFigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8996305/v1/ebe144ff416287e4347b2999.docx"},{"id":106436668,"identity":"d972994c-c97c-47ab-a25e-d874bb3cce56","added_by":"auto","created_at":"2026-04-08 13:58:59","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1008405,"visible":true,"origin":"","legend":"Regional association plots for three loci that gain significance with the inclusion of Colombian samples.","description":"","filename":"SupplementaryFigure2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8996305/v1/1e9212ac88f26b3c0c07a5d6.docx"},{"id":106436671,"identity":"3ecfd172-18ef-4dcd-ab94-24e812674731","added_by":"auto","created_at":"2026-04-08 13:58:59","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":397786,"visible":true,"origin":"","legend":"Polygenic risk score (PRS) model fit (R\u0026#x00B2;) across multiple \u003ci\u003eP\u003c/i\u003e-value thresholds (PT) in the Colombian cohort.","description":"","filename":"SupplementaryFigure3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8996305/v1/d0a9bdce6e0ec0b4016744d0.docx"},{"id":106436669,"identity":"3314a40b-1c68-464c-9acb-9166f184ac51","added_by":"auto","created_at":"2026-04-08 13:58:59","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":165234,"visible":true,"origin":"","legend":"Linear regression model (LRM) showing the relationship between PRS and Native American (NAM) ancestry, based on 73 EADB genome-wide significant SNPs reported in Bellenguez et al. 2022.","description":"","filename":"SupplementaryFigure4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8996305/v1/ad3469ab3dedb3a589e03a0a.docx"},{"id":106724078,"identity":"0bbfa09a-0d3b-4d19-b4bb-990a2b423be3","added_by":"auto","created_at":"2026-04-12 18:25:30","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":71221,"visible":true,"origin":"","legend":"Supplementary tables","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8996305/v1/ffd043c62109867f986c2d1d.xlsx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Genome-wide association meta-analysis of Alzheimer's disease in Colombian, Argentinian, and Chilean populations","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8996305/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8996305/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Latin American populations are underrepresented in Alzheimer’s disease (AD) genome-wide association studies (GWAS), limiting ancestry-specific risk prediction. To address this gap, a GWAS was conducted with 254 AD cases and 241 controls from Colombia, followed by a trans-ancestry meta-analysis that incorporated cohorts from Colombia, Chile, Argentina, and the European EADB consortium. AD polygenic risk scores (AD-PRS) derived from the Latin American GWAS were compared with those from European GWAS. \u003ci\u003eAPOE\u003c/i\u003e-ε4 showed the strongest association in Colombians (OR=3.33, \u003ci\u003eP\u003c/i\u003e=1.81×10\u003csup\u003e-9\u003c/sup\u003e). The meta-analysis identified five loci, including a population-specific signal at \u003ci\u003eFBXO33/MIA2\u003c/i\u003e (OR=1.09, \u003ci\u003eP\u003c/i\u003e=8.39×10\u003csup\u003e-9\u003c/sup\u003e). Additionally, a missense coding variant at \u003ci\u003eGCAT\u003c/i\u003e, first identified in a Caribbean Hispanic cohort with enriched Native American ancestry (NAM), was validated in our admixed population with strong NAM ancestry (OR=2.55, \u003ci\u003eP\u003c/i\u003e=1.00×10\u003csup\u003e-4\u003c/sup\u003e). The accuracy of European-derived AD-PRSs was largely driven by \u003ci\u003eAPOE\u003c/i\u003e and declined with increasing NAM, whereas Latin American-derived AD-PRS captured ancestry-specific polygenic risk beyond \u003ci\u003eAPOE\u003c/i\u003e adjustment. These findings indicate that AD risk in Colombians reflects both shared and ancestry-specific genetic effects. In addition, our results suggest that genetic datasets from admixed Latin American populations are beginning to reach the scale and resolution necessary not only to replicate established AD loci but also to identify population-specific variants, including novel signals and refined associations at previously implicated loci. These results underscore the importance of ancestry-matched GWAS and PRS development to achieve equitable and biologically accurate AD risk prediction.","manuscriptTitle":"Genome-wide association meta-analysis of Alzheimer's disease in Colombian, Argentinian, and Chilean populations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-08 13:58:55","doi":"10.21203/rs.3.rs-8996305/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-28T17:54:38+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-04-28T17:37:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-03T17:15:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-03T16:48:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Psychiatry","date":"2026-03-02T13:32:12+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2026-03-02T11:54:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"84bd3343-393c-4290-b1f3-6f2adbd37a1e","owner":[],"postedDate":"April 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":63863690,"name":"Biological sciences/Genetics"},{"id":63863691,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-04-28T17:40:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-08 13:58:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8996305","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8996305","identity":"rs-8996305","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}