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We aimed to: (1) evaluate the predictive performance of polygenic risk scores (PRSs) for glycaemic traits from childhood to early adulthood; (2) identify gene\u2013environment interactions shaping glucose homeostasis trajectories; and (3) explore underlying mechanisms using pathway-specific PRSs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Data from 8783 participants (aged 7\u201324 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to compute 12 PRSs for type 2 diabetes, fasting glucose, insulin and BMI. Glycaemic outcomes, including insulin resistance, prediabetes (impaired fasting glucose) and type 2 diabetes, were assessed using fasting glucose and insulin (ages 7, 15, 18 and 24 years) and HbA\n                      <jats:sub>1c<\/jats:sub>\n                      (age 9 years). We evaluated whether PRSs could distinguish between transient (resolved by adulthood) and persistent glycaemic abnormalities using multinomial regression. We performed univariate and multivariate regressions, incorporating environmental factors (lifestyle, diet and maternal characteristics), and evaluated model performance using R\n                      <jats:sup>2<\/jats:sup>\n                      and AUC. We tested interactions between PRS quintiles and environmental factors and explored pathophysiological mechanisms using pathway-specific PRSs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Prediabetes prevalence was up to 24% at age 24 years. PRS-enhanced models outperformed those using environmental factors alone (e.g. AUC for dysglycaemia at age 15 improved by 0.12, reaching 0.78). Fasting glucose PRS showed moderate ability to differentiate transient from persistent prediabetes (AUC=0.70). Gene\u2013environment analyses revealed that high genetic risk combined with increased screen time or younger maternal age increased insulin resistance risk. Physical activity and health awareness attenuated this risk. Pathway analyses indicated insulin secretion as a key mechanism earlier in life, with insulin resistance emerging later.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Genes interact with environment to define glucose homeostasis in youth, highlighting modifiable factors as actionable targets for early prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06722-5","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:19:34Z","timestamp":1776277174000},"page":"1962-1974","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nature vs nurture of glucose homeostasis trajectories in children from the ALSPAC study"],"prefix":"10.1007","volume":"69","author":[{"given":"Isabel","family":"Gamache","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaossarath","family":"Fagbemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soren","family":"Harnois-Leblanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia M. 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Int J Obes 34(2):S24-31. https:\/\/doi.org\/10.1038\/ijo.2010.236","journal-title":"Int J Obes"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06722-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06722-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06722-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:41:15Z","timestamp":1780584075000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06722-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":43,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["6722"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06722-5","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]},"assertion":[{"value":"3 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This research was enabled in part by support provided by Calcul Qu\u00e9bec and the Digital Research Alliance of Canada (alliancecan.ca). Some of the data were presented as an abstract and oral presentations at the American Society of Human Genetics (ASHG) meeting in 2024, as well as at the Montr\u00e9al Genomics Meeting and the International Society for Paediatric and Adolescent Diabetes (ISPAD) meeting in 2025.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"ALSPAC data were available under the project number B-3723. Data on glycaemic traits generating PRSs from the GWAS cohort have been contributed by MAGIC investigators and have been downloaded from\n                      \n                      . Sources for all PRSs are indicated in ESM Table\n                      \n                      .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"All references about software and R packages used across the manuscript can be found in ESM Table\n                      \n                      .","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Software information & Supplementary tables"}},{"value":"The UK Medical Research Council and Wellcome (Grant ref: 217065\/Z\/19\/Z) and the University of Bristol provide core support for ALSPAC.\u00a0DM received research funding from the Canadian Institutes of Health Research (CIHR; application number EA6-201120) and is a Junior 2 Scholar supported by the Fonds de recherche du Qu\u00e9bec\u2013Sant\u00e9 (FRQS). MH holds a Senior Investigator Award from the FRQS. SHL is supported by the ADA (grant number 7-23-PDFT2DY-3) and the Pyle Fellowship Award from the Department of Population Medicine at Harvard Medical School and the Harvard Pilgrim Health Care Institute.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"MH is Chair of the Scientific Committee on Obesity Prevention at the Institut national de sant\u00e9 publique du Qu\u00e9bec. She is also a member of the Advisory Group on the Management of Obesity in Children and Adolescents and the Qu\u00e9bec Advisory Committee on Bariatric Medicine for the Qu\u00e9bec Minister of Health and Social Services, and a member of the Professional Council of Diab\u00e8te Qu\u00e9bec. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their contribution to this manuscript.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"All authors participated in the conception of the study. Both IG and KF performed formal analysis, investigation and writing of the original draft. IG performed the software, visualisation and data curation. DM, CMTG and MH participated in the funding acquisition. SHL, CMTG, MH and AVH participated in the methodology. NJT provided resources and methodology. All authors provided substantial contributions to the analysis and interpretation, reviewed the article critically, and approved the final version. This publication is the work of the authors and DM will serve as guarantor for the contents of this paper.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}