Genetic insights and mechanistic parallels in gestational diabetes mellitus and type 2 diabetes

Gestational diabetes mellitus (GDM) has a high heritability and frequently co-occurs with type 2 diabetes (T2D), indicating shared genetic mechanisms. Firstly, we employed RHOGE to ascertain the genetic correlation and putative causal directions between GDM and T2D. Subsequently, the Genotype-Tissue Expression Project v8 eQTls files and the FinnGen R11 dataset were employed to conduct cross-tissue transcriptome association studies, Functional Summary-based Imputation in single tissues, and Gene Analysis combined with Multimarker Analysis of Genomic Annotation for GDM and T2D, respectively. A total of 5 genes were identified as GDM susceptibility and 97 genes linked to T2D susceptibility. Of these, four genes (COBLL1, NRBP1, IFT172 and TRIM54) were identified as being shared. Mendelian randomization and colocalization analyses revealed the causal associations of them with GDM and T2D in distinct tissues. Subsequent analyses indicated COBLL1 may influence GDM and T2D risk by regulation of actin filament polymerization and interactions with chemical responses. NRBP1 may confer protective effects against diabetes through regulation of insulin secretion, while IFT172 and TRIM54 may play a role in energy balance signaling and metabolism of skeletal muscle, respectively. Our study provides insight into the shared genetic mechanism between GDM and T2D and identifies potential targets for pharmacological intervention.