{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T05:18:13Z","timestamp":1784438293224,"version":"3.55.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Observational studies have reported that patients with Alzheimer\u2019s disease (AD) have a greater burden of comorbidities typically associated with stress-related psychiatric disorders. However, the contribution of hereditary factors to this comorbidity remains unclear. We evaluated phenotypic associations using observational data from the UK Biobank.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Our study focused on investigating the shared risk variants and genetic etiology underlying AD and three stress-related psychiatric disorders: post-traumatic stress disorder, anxiety disorder, and major depressive disorder. By leveraging summary statistics from genome-wide association studies, we investigated global genetic correlations using linkage disequilibrium score regression, genetic covariance analysis, and high-definition likelihood. Genome-wide cross-trait analysis with association analysis based on subsets and cross-phenotype association were performed to discover genome-wide significant risk variants shared between AD and the three stress-related psychiatric disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A significant positive genetic correlation was observed between AD and major depressive disorder using linkage disequilibrium score regression (rg = 0.231; <jats:italic>P<\/jats:italic> = 0.018), genetic covariance analysis (rg = 0.138; <jats:italic>P<\/jats:italic> &amp;lt; 0.001), and high-definition likelihood (rg = 0.188; <jats:italic>P<\/jats:italic> &amp;lt; 0.001). Association analysis based on subsets and cross-phenotype association revealed thirteen risk variants in six genes shared between AD and post-traumatic stress disorder; seven risk variants in four genes shared between AD and anxiety disorder; and 23 risk variants in four genes shared between AD and major depressive disorder. Functional annotation and gene-set enrichment analysis indicated that 12 genes for comorbidity shared between patients with AD and all three stress-related psychiatric disorders were enriched in the spleen, pancreas, and whole blood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results advance our knowledge of the shared genetic origins of comorbidities and pave the way for advancements in the diagnosis, management, and prevention of stress-related AD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fragi.2025.1488528","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T14:31:41Z","timestamp":1738765901000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Investigating shared risk variants and genetic etiology between Alzheimer\u2019s disease and three stress-related psychiatric disorders: a large-scale genome-wide cross-trait analysis"],"prefix":"10.3389","volume":"6","author":[{"given":"Weijia","family":"Dang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqi","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hualin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalu","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deqiang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1186\/s12967-023-04107-5","article-title":"Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new independent variants","volume":"21","author":"Alemany","year":"2023","journal-title":"J. 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