Cross-ancestry analysis of gestational diabetes mellitus identifies novel loci, drug targets and biological pathways
Abstract
Background: 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).
Methods: 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.
Results: 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.
Conclusion: 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…
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