Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Abstract

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10−8) with GDM, mapping to/near MTNR1B (p = 4.3x10−54), TCF7L2 (p = 4.0x10−16), CDKAL1 (p = 1.6 × 10−14), CDKN2A-CDKN2B (p = 4.1x10−9) and HKDC1 (p = 2.9x10−8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

“…T2D is characterized by persistently high blood glucose levels due to impaired insulin secretion from pancreatic β cells, insensitivity to insulin in peripheral tissues, and increased glucose production in the liver 107 . Several well-established genetic risk factors for T2D are variants in the transcription factor 7-like 2 (TCF7L2) gene 108-110 that drive expression of functional splice isoforms of this gene 109,111 . The protein product of this gene is the high mobility group box-containing transcription factor TCF7L2 which activates Wnt signaling with tissue-specific outcomes 108,112-114 .…”

Evaluating the Causal Effects of Gestational Diabetes Mellitus, Heart Disease, and High Body Mass Index on Maternal Alzheimer’s Disease and Dementia: Multivariable Mendelian Randomization

“…Third, we acknowledged the lack of power in the GWAS database of GDM. Compared with the current GWAS database of GDM ( Pervjakova et al, 2022 ), the GDM database we collected only included 2062 GDM women, which might influence the statistical power of our MR results as we just extracted only two independent SNPs of GDM. We hope to include more GWAS studies with this complications in the future.…”

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes in up to 497,932 women

“…36 Other observational studies using multivariable regression have reported that maternal BMI is associated with higher risk of stillbirths 37 , induction 38 , caesarean section 38 , and not initiating breastfeeding. 39 Previous Mendelian randomization studies have focused on a limited set of outcomes and are supportive of higher maternal BMI being related to higher mean offspring birthweight 4,40,41 (N ∼ 9,000 to 400,000) and GDM 42 (N = 5,485 cases and 347,856 controls).…”