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

  1. Binur Orazumbekova
  2. Julia Zöllner
  3. Sam Hodgson
  4. Margherita Bigossi
  5. Miriam Samuel
  6. Genes and Health Research Team
  7. Sarah Finer
  8. Rohini Mathur
  9. Moneeza K Siddiqui
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Abstract

Aims

We 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.

Methods

In 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.

Results

A 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.

Conclusions

These 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 context

What is already known about this subject?

  • South Asians develop type 2 diabetes, on average, a decade earlier than white Europeans and at lower BMI levels.

  • The 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.

  • The contribution of adiposity-related polygenic scores (PGS) to type 2 diabetes onset has not been examined across ancestries.

What is the key question?

  • What is the association between adiposity PGS and type 2 diabetes onset across ancestries, what how much of this effect is mediated by BMI?

What are the new findings?

  • Higher 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.

  • Other PGS for central adiposity are significant predictors of early type 2 diabetes onset and central adiposity anthropometrics in south Asians.

How might this impact on clinical practice in the foreseeable future?

  • These 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.

Article activity feed

  1. Version published to 10.1101/2025.06.12.25329480v1 on medRxiv