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In this field, \u2018brain age gap\u2019 has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual\u2019s biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of 23\u201329% attributable to common genetic variants and highlighted 59 associated loci (39 novel). The leading locus encompasses <jats:italic>MAPT<\/jats:italic>, encoding the tau protein central to Alzheimer\u2019s disease. Genetic correlations revealed relationships with mental health, physical health, lifestyle and socioeconomic traits, including depressed mood, diabetes, alcohol intake and income. Mendelian randomization indicated a causal role of high blood pressure and type 2 diabetes in accelerated brain aging. Our study highlights key genes and pathways related to neurogenesis, immune-system-related processes and small GTPase binding, laying the foundation for further mechanistic exploration.<\/jats:p>","DOI":"10.1038\/s43587-025-00962-7","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T09:03:42Z","timestamp":1759482222000},"page":"2086-2103","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Genome-wide analysis of brain age identifies 59 associated loci and unveils relationships with mental and physical health"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2994-3075","authenticated-orcid":false,"given":"Philippe","family":"Jawinski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Forstbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-7950","authenticated-orcid":false,"given":"Holger","family":"Kirsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5401-852X","authenticated-orcid":false,"given":"Frauke","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2604-2404","authenticated-orcid":false,"given":"Arno","family":"Villringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9054-6688","authenticated-orcid":false,"given":"A. 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