Partitioned polygenic scores highlight role of beta-cell function and unfavourable fat distribution patterns in young onset type 2 diabetes in south Asians

South Asians experience a higher risk of early-onset Type 2 diabetes (T2D) with normal BMI. However, since genetic research is largely focussed on white Europeans, the reasons for this are poorly understood. We used 12 recently derived multi-ancestry partitioned polygenic risk scores (pPS) to identify the aetiological pathways underlying T2D, gestational diabetes mellitus (GDM), earlier onset, progression to complications and insulin dependence, and treatment response in a south Asian cohort. Using electronic health record and genetic data from 51,108 British Pakistani and Bangladeshi individuals with T2D (n = 11,673) and GDM (n = 1,965) in the Genes & Health study, we explored associations between pPS, T2D, GDM, diabetes complications, and treatment response using sex- and ancestry-adjusted multivariable regression and Cox proportional-hazards models. A pPS representing insulin deficiency was most strongly associated with T2D per standard deviation (OR: odds ratio):1.46, 95%CI:1.42–1.50), GDM (OR:1.27, 95%CI: 1.20–1.34) and age at T2D diagnosis (beta = -1.7 years, 95%CI: -1.5 to -1.9), followed by a pPS representing an unfavourable fat distribution (lipodystrophy). Individuals at high genetic risk of both insulin deficiency and lipodystrophy were diagnosed with T2D 8.2 years earlier with BMI 3 kg/m ² lower compared to those at low genetic risk. The insulin deficiency pPS was associated with poorer response to metformin, thiazolidinediones, and SGLT2 inhibitors (post-treatment HbA1c increased from baseline by 0.51%, 1.83%, and 1.13% respectively). Higher Insulin deficiency and lipodystrophy pPS were also associated with faster progression to insulin dependence and microvascular complications. Using UK Biobank, we found that south Asians had a greater genetic burden of both these pPS compared to white Europeans. In British Pakistani and Bangladeshi individuals, genetic predisposition to insulin deficiency and lipodystrophy helps identify individuals at risk of earlier onset of type 2 diabetes, who progress faster to complications and insulin dependence, and are less likely to respond to standard diabetes management pathways.