Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

2 型糖尿病可重复地分为五种亚型，具有不同的疾病进展和并发症风险；然而，病因差异尚不清楚。我们使用全基因组关联和遗传风险评分 (GRS) 分析来比较潜在的遗传驱动因素。瑞典 ANDIS（斯堪尼亚的所有新糖尿病患者）研究中的个体与没有糖尿病的个体进行了比较；芬兰 DIREVA（瓦萨糖尿病登记处）和 Botnia 研究被用于复制。我们表明，亚型在糖尿病家族史以及与 GRS 与糖尿病相关特征的关联方面存在差异。严重的胰岛素抵抗亚型与空腹胰岛素的 GRS 唯一相关，但与TCF7L2中的变体无关位点或 GRS 反映胰岛素分泌。此外，LRMDA 附近的 SNP (rs10824307)与轻度肥胖相关糖尿病具有独特的相关性。因此，我们得出结论，这些亚型具有部分不同的遗传背景，表明病因差异。