Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

Gestational diabetes mellitus (GDM) affects [~]14% of pregnancies and is linked to adverse pregnancy outcomes and increased maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium conducted trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identified 37 GDM-associated loci (19 novel) and five novel loci for glycemic traits, all operating through the maternal genome. Most GDM loci overlapped with T2DM and non-pregnant glycemic traits, with limited evidence for pregnancy-specific effects. MTNR1B showed pregnancy-enhanced effects on 2-hour glucose, potentially mediated by interaction with GPR61, a novel GDM locus, suggesting a gestation-specific melatonin-glucose signalling axis. We also observed ancestry-specific effects at the fasting glucose locus ABCB11, with opposite directions in European and East Asian populations. Our findings provide new insights into the genetic architecture of GDM and highlight the need for larger, ancestrally diverse studies.