Research Article: Cross-ancestry analysis of gestational diabetes mellitus identifies novel loci, drug targets and biological pathways
Abstract:
Gestational diabetes mellitus (GDM) is a common pregnancy complication with adverse maternal and fetal outcomes, yet its genetic basis is not fully understood. Previous genome-wide association studies (GWAS) have identified only a limited number of susceptibility loci, most of which overlap with genes for type 2 diabetes (T2D).
We performed a meta-analysis of GWAS datasets from British, Finnish, and Chinese populations to identify novel genetic susceptibility loci for GDM. Functional annotation of associated variants was conducted using FUMA. We assessed cross-population genetic correlations (Popcorn) and fine-mapped ancestry-specific signals (SuSiEx). Candidate gene was then prioritized using multiple approaches, including eQTL mapping, MAGMA, TWAS-Fusion, GCTA-mBAT, and PoPs. Finally, we integrated proteomic data from BLISS and performed in-depth pathway and tissue enrichment analyses using MAGMA and GSA-MiXeR.
Our multi-pronged approach identified two novel susceptibility genes associated with GDM risk: ELL2 and ATRAID . In addition, three enriched biological pathways linked to GDM loci were discovered, including: the regulation of hexokinase activity, the regulation of insulin, and the regulation of protein.
Our study links the expression of ELL2 and ATRAID with the risk of GDM, and identifies three GDM-related enriched pathways. These findings provide new insights into the pathogenesis of GDM and highlights potential new targets for future research and therapeutic intervention.
Introduction:
Gestational diabetes mellitus (GDM) is a common pregnancy complication with adverse maternal and fetal outcomes, yet its genetic basis is not fully understood. Previous genome-wide association studies (GWAS) have identified only a limited number of susceptibility loci, most of which overlap with genes for type 2 diabetes (T2D).
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