{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T07:42:07Z","timestamp":1785656527873,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,4]]},"group-title":"Genetic and Genomic Medicine","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer\u2019s disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Apart from the\n                    <jats:italic>APOE<\/jats:italic>\n                    region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes\/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene\n                    <jats:italic>PAX7<\/jats:italic>\n                    in ADRD cases and controls.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.01.26352216","type":"posted-content","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T23:05:14Z","timestamp":1777935914000},"source":"Crossref","is-referenced-by-count":1,"title":["A Genome-wide Association Study of Alzheimer\u2019s Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci"],"prefix":"10.64898","author":[{"given":"Richard","family":"Sherva","sequence":"first","affiliation":[{"name":"National Center for PTSD, Behavioral Sciences Division, VA Boston Healthcare System, Boston, MA, 02130"},{"name":"Department of Medicine (Biomedical Genetics) Boston University Chobanian & Avedisian, School of Medicine, Boston, MA, 02118, 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University Chobanian & Avedisian, School of Medicine, Boston, MA"},{"name":"Boston University Alzheimer\u2019s Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Miller","sequence":"additional","affiliation":[{"name":"National Center for PTSD, Behavioral Sciences Division, VA Boston Healthcare System, Boston, MA, 02130"},{"name":"Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debby","family":"Tsuang","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Wolf","sequence":"additional","affiliation":[{"name":"National Center for PTSD, Behavioral Sciences Division, VA Boston Healthcare System, Boston, MA, 02130"},{"name":"Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zeng","sequence":"additional","affiliation":[{"name":"VA Washington DC Healthcare System, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Le Guen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA"},{"name":"Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Tejeda","sequence":"additional","affiliation":[{"name":"Department of Medicine (Biomedical Genetics) Boston University Chobanian & Avedisian, School of Medicine, Boston, MA, 02118, 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