PhD Scientific Days 2026

Theoretical and Translational Medicine 1.

Maternal and Fetal Gene Variants Associated with Gestational Diabetes Mellitus: Evidence from a Mega Genome-Wide Association Study

Name of the presenter

Nemes, András Botond

Institute/workplace of the presenter

Semmelweis University, Institute of Clinical Pathophysiology

Authors

Nemes András Botond¹, Dr. Nádasdi Ákos¹, Dr. Németh László¹, Prof. Dr. Benyó Zoltán¹, Dr. Firneisz Gábor¹
1: Semmelweis University, Institute of Clinical Pathophysiology

Text of the abstract

Background:
Numerous genome-wide association studies (GWAS) have examined maternal genetic effects on the development of gestational diabetes mellitus (GDM). Our aim was to investigate both maternal and fetal genetic factors associated with GDM in a large GWAS, with particular focus on fetal genetic contributions, which have remained largely unexplored to date.
Methods:
In a multi-ancestry mega-GWAS, we analyzed data of 4,997 mother–child pairs from the international, multiethnic, population-based landmark HAPO study (phs000096/T2DMBIRTHWT, NIH dbGaP; with approved access). Following quality control, haplotype phasing and subsequent imputation were performed using the 1000 Genomes Phase 3 v5 reference panel (SNVfinal n = 8.7M). We used additive genetic model and Plink 2.0 software on the complete case database (n=3505). The effective number of independent variants (Meff) was used to determine the Bonferroni-corrected significance threshold (p = 5.0 × 10⁻⁷). All analyses were adjusted for the following covariates: pre-pregnancy maternal BMI, maternal age, gestational weight gain, and ancestry. GDM was diagnosed according to the IADPSG (WHO 2013) criteria.
Results:
The number of complete cases was 3,505 (European: 1,224; Hispanic: 532; Afro-Caribbean: 597; Thai: 1,152). The mean maternal age was 28.8 years, and the proportion of overweight and obese mothers was 22.3% and 15.4%, respectively. Among maternal variants, four novel associations with GDM were identified (intronic variants in PCSK5, CCBE1, and FAM19A5, and one intergenic variant). After adjustment, three additional novel associations were detected: one variant located in an enhancer region and two intergenic variants. We also identified novel fetal variants associated with GDM development: two intronic variants (in ELAVL2, ABCC8 genes) and one intergenic variant. No overlap was observed between the maternal and fetal variants associated with GDM.
Conclusion:
To our best knowledge we first report in a large-scale GWAS that fetal genetic variants associated with the development of GDM. In addition, we described seven novel genetic associations influencing GDM risk, which remained significant after adjustment for key clinical covariates