研究人员使用全基因组关联和遗传风险评分（GRS）分析来比较了潜在的遗传驱动因素。来自瑞典ANDIS（All New Diabetics In Scania）研究的个体与无糖尿病的个体进行了比较；芬兰DIREVA（Diabetes register in Vasa）和Botnia研究被用来进行重复。结果表明，亚型在糖尿病家族史和与糖尿病相关特征的GRS方面存在差异。严重的胰岛素抵抗亚型与空腹胰岛素的GRS独特相关，但与TCF7L2基因座的变体或反映胰岛素分泌的GRS无关。
Title: Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes
Author: Mansour Aly, Dina, Dwivedi, Om Prakash, Prasad, Rashmi B., Krjmki, Annemari, Hjort, Rebecka, Thangam, Manonanthini, kerlund, Mikael, Mahajan, Anubha, Udler, Miriam S., Florez, Jose C., McCarthy, Mark I., Brosnan, Julia, Melander, Olle, Carlsson, Sofia, Hansson, Ola, Tuomi, Tiinamaija, Groop, Leif, Ahlqvist, Emma
Abstract: 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. Genome-wide association and genetic risk score analyses highlight differences in genetic architecture across five subtypes of diabetes.