India’s type 2 diabetes subgroup polygenic scores 2023
Using a machine learning approach, researchers were able to classify Europeans with diabetes into five distinct subgroups based on their underlying genetic causes: severe autoimmune diabetes (SAID), severe insulin deficiency (SIDD), severe insulin resistance (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD).
In the past, we have confirmed four of the Indian WellGen study’s non-autoimmune subgroups in young adults with T2D. Here, we sought to test the applicability of European-derived centroids and genetic risk scores (GRSs) on the unselected (for age) WellGen in order to delve into the genetic aetiology of the Indian T2D subgroups.
Methods
T2D subjects of Indian origin (WellGen, n = 2217, 821 genotyped) were compared to normal glucose tolerant controls (Pune Maternal Nutrition Study, n = 461) using centroids and GRSs developed in Europe.
Findings
The most common subgroup was SIDD, followed by MOD, with SIRD and MARD being far less common. T2D, obesity, and lipid characteristics with a weighted-GRS. Previous links between T2D-related GRS, insulin secretion, and body mass index and sudden infant death syndrome and metabolic disorder were confirmed.
In contrast to Europeans, Indian subgroups showed associations between GRS for (a) proinsulin and MOD and MARD, (b) liver-lipids and SIDD, SIRD, and MOD, and (c) an inverse impact of beta-cell GRS with SIDD and MARD, and obesity GRS with MARD. Indians, but not Europeans, showed an association between T2D and MOD and genetic variations of fucosyltransferases.
Interpretation
While the similarities highlight the need for large-scale studies to identify aetiologies in diverse ancestries, the differences highlight the importance of tailoring some of the European-derived GRSs to T2D and its subgroups in India. The statistics are consistent with separate genetic causes for each type 2 diabetes subgroup, as is also found in Europe.
Funding
Wellcome Trust, Crafoord Foundation, Albert P. Hlsson Foundation, DST (India), Diabetes Wellness, and Hjärt-Lungfonden (all from Sweden), and the Vetenskapsrdet (Sweden).
