BMI inadequately mediates the relationship between polygenic risk of adiposity and early onset type 2 diabetes in south Asians

AimsWe investigated the relationship between polygenic score (PGS) for BMI and other adiposity PGS with age at type 2 diabetes onset in white European (EUR) and south Asian (SAS) ancestries, and the mediating role of BMI. MethodsIn this retrospective study, using polygenic score (PGS) for BMI, clinically measured BMI and age at type 2 diabetes onset, we conducted mediation analysis separately for SAS (n=3,901, Genes & Health) and EUR (n=729, UK Biobank) aged 40 years or older. For SAS, we also used multivariable linear regression with backward selection to identify the best adiposity PGS (waist circumference (WC), waist-to-hip ratio (WHR), visceral adipose tissue (VAT), body fat (BF), trunk fat (TF) and gluteofemoral fat (GFAT), hand-grip strength (HGS)) predicting age at type 2 diabetes onset. ResultsA one SD increment in BMI-PGS was associated with earlier type 2 diabetes onset by -0.73 years (95%CI -1.01; -0.45) in SAS and -0.57 years (95%CI -1.05; -0.08) in EUR. BMI fully mediated the PGS effect in EUR (100%) and only partially in SAS (28%). Alongside BMI-PGS, WC-PGS and TF-PGS were good at discriminating measured BMI, WC and WHTR in SAS and were correlated with BMI-PGS. Other best predictors of early onset type 2 diabetes in SAS were WC-PGS, WHR-PGS, BF-PGS and GFAT-PGS, which differed between SAS subgroups and by sex. ConclusionsThese findings underscore the importance of incorporating adiposity-related genetics in predicting type 2 diabetes onset among SAS and demonstrate the limitations of using BMI alone to capture associated risk, particularly in diverse populations with typically lower BMI. Research in contextWhat is already known about this subject? O_LISouth Asians develop type 2 diabetes, on average, a decade earlier than white Europeans and at lower BMI levels. C_LIO_LIThe well-established association between BMI and type 2 diabetes risk in white Europeans is more complex in south Asians, who have different patterns of adipose tissue distribution that are not well reflected in BMI. C_LIO_LIThe contribution of adiposity-related polygenic scores (PGS) to type 2 diabetes onset has not been examined across ancestries. C_LI What is the key question? O_LIWhat is the association between adiposity PGS and type 2 diabetes onset across ancestries, what how much of this effect is mediated by BMI? C_LI What are the new findings? O_LIHigher BMI-PGS is associated with earlier type 2 diabetes onset in both south Asians and white Europeans; this relationship is fully mediated by BMI in white Europeans but only partially in south Asians. C_LIO_LIOther PGS for central adiposity are significant predictors of early type 2 diabetes onset and central adiposity anthropometrics in south Asians. C_LI How might this impact on clinical practice in the foreseeable future? O_LIThese findings highlight the importance of incorporating adiposity-related genetics in predicting type 2 diabetes onset in diverse populations and underscore the need to move beyond BMI when assessing metabolic risk and potentially evaluating the effectiveness of interventions. C_LI