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This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO\u2010defined T2D subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Using 74\u2009795 European\u2010ancestry participants from the UK Biobank, we performed genome\u2010wide association studies (GWAS) of relatively early\u2010onset T2D (eoT2D; AAO &lt;\u200955\u2009years) and late\u2010onset T2D (loT2D; AAO \u2265\u200970\u2009years). We investigated subtype\u2010specific genetic loci, SNP\u2010based heritability, genetic correlations, Mendelian randomization (MR)\u2010based relationships, polygenic risk scores (PRS) and phenome\u2010wide association studies (PheWAS). Single\u2010cell transcriptomic data from human pancreatic tissues were further used to evaluate cell\u2010type\u2010specific expression patterns of candidate genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SNP\u2010based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to \u03b2\u2010cell function and insulin regulation, including\n                      <jats:italic>SLC30A8<\/jats:italic>\n                      and\n                      <jats:italic>IRS1<\/jats:italic>\n                      . By contrast, loT2D showed a comparatively lipid\u2010related genetic profile, featuring\n                      <jats:italic>APOE<\/jats:italic>\n                      \u2010associated signals and expression patterns in immune\u2010related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype\u2010specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Extreme AAO\u2010defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age\u2010stratified genetic risk assessment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71302","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:46:53Z","timestamp":1788936413000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2010Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early\u2010Onset and Late\u2010Onset\n                    <scp>T2D<\/scp>"],"prefix":"10.1111","author":[{"given":"Ben","family":"Niu","sequence":"first","affiliation":[{"name":"The Children Hospital of Soochow University, School of Public Health, Suzhou Medical College Soochow University  Suzhou Jiangsu People's Republic of China"},{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College of Soochow University  Suzhou Jiangsu People's Republic of China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non\u2010Communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology Soochow University  Suzhou Jiangsu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2010Hui","family":"Xia","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College of Soochow University  Suzhou Jiangsu People's Republic of China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non\u2010Communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology Soochow University  Suzhou Jiangsu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Xin","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College of Soochow University  Suzhou Jiangsu People's Republic of China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non\u2010Communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology Soochow University  Suzhou Jiangsu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei\u2010Yan","family":"Deng","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College of Soochow University  Suzhou Jiangsu People's Republic of China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non\u2010Communicable Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology Soochow University  Suzhou Jiangsu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Genetic Metabolism, Children Hospital of Soochow University  Suzhou Jiangsu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1453-8082","authenticated-orcid":false,"given":"Shu\u2010Feng","family":"Lei","sequence":"additional","affiliation":[{"name":"The Children Hospital of Soochow University, School of Public Health, Suzhou Medical College Soochow University  Suzhou Jiangsu 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