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We aimed to quantify the overall contribution of obesity and modifiable lifestyle factors to the association between genetic predisposition to adiposity and the development of T2D.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This prospective cohort study involved 220 703 White British participants from the UK Biobank. It examined the associations between genetic predisposition to adiposity [body mass index polygenic risk (BMI-PRS) and waist\u2013hip ratio polygenic risk (WHR-PRS)] and incident T2D, as well as interactions and mediation via lifestyle factors (diet quality, physical activity levels, total energy intake, sleep duration, and smoking and alcohol intake) and phenotypic adiposity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>People with high phenotypic adiposity and high adiposity PRS values (&amp;gt;1 SD above the mean) had the highest risk of incident T2D (versus non-obese\/central obese and non-high PRS). This was the case for BMI-PRS [hazard ratio (HR) = 3.72] and WHR-PRS (HR = 4.17). Lifestyle factors explained 30.5% of the BMI-PRS\/T2D association (2.0% mediation; 28.5% effect modification), and lifestyle and obesity together explained 92.1% (78.8% mediation; 13.3% effect modification). Lifestyle factors explained 20.4% of the WHR-PRS\/T2D association (3.4% mediation; 17.0% effect modification), and lifestyle and central obesity together explained 72.8% (41.1% mediation; 31.7% effect modification).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Whilst phenotypic adiposity explains a large proportion of the association between BMI-PRS\/WHR-PRS and T2D, modifiable lifestyle factors also make contributions. Promoting healthy lifestyles among people prone to adiposity is important in reducing the global burden of T2D.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ejendo\/lvaf084","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T07:39:46Z","timestamp":1745393986000},"page":"549-557","source":"Crossref","is-referenced-by-count":11,"title":["Genetic predisposition to adiposity, and type 2 diabetes: the role of lifestyle and phenotypic adiposity"],"prefix":"10.1093","volume":"192","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2391-4416","authenticated-orcid":false,"given":"Mengrong","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Health and Wellbeing, University of Glasgow, Glasgow G12 8TB ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joey","family":"Ward","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing, University of Glasgow, Glasgow G12 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