Gestational Diabetes Mellitus and Birth Weight: A Bidirectional Mendelian Randomization and Cohort Study in China.
- 1Department of Women Health, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center of Nanjing Medical University, Changzhou, Jiangsu, 213003, People's Republic of China.
- 2Department of Obstetrics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center of Nanjing Medical University, Changzhou, Jiangsu, 213003, People's Republic of China.
- 3Department of Medical Genetics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center of Nanjing Medical University, Changzhou, Jiangsu, 213003, People's Republic of China.
Abstract
Gestational diabetes mellitus (GDM) is regarded as a driver of fetal macrosomia, yet observational estimates of its effect on birth weight (BW) are vulnerable to confounding. Whether GDM causally shapes fetal growth, and through which shared biology, remains unresolved. We performed a bidirectional two-sample Mendelian randomization (MR) using FinnGen R11 GDM (16,802 cases) and the EGG Consortium birth-weight GWAS (n=286,868), with inverse-variance weighted (IVW, primary), MR-Egger, weighted median, weighted mode, RAPS estimators, MR-PRESSO and Bayesian colocalization. Multi-omics evidence (GSE92772, ST001948, INTERVAL cis-pQTLs) was integrated as hypothesis-generating evidence. In a cohort of 24,448 singleton pregnancies, linear and logistic regression, bootstrap mediation, and double/debiased machine learning (DML) were performed for verification. The primary IVW estimate for GDM to BW was null (β=-0.004, P=0.889) under extreme heterogeneity, and robust estimators showed nominally positive signals. Seven of 21 instruments flagged as outliers overlapping six colocalizing loci. Therefore, it is impossible to precluding a reliable causal interpretation. Reverse MR (BW to GDM) was exploratory (five instruments, all outliers). Colocalization identified six loci (CCND2, MTNR1B, GPSM1, ADCY5, CDKAL1, TCF7L2) with evidence of a shared causal variant (PP.H4≥0.5). All established islet beta-cell/insulin-secretion genes suggested shared upstream biology. In the cohort, GDM was associated with higher rates of macrosomia (OR 1.21) and lower birth weight (LBW, OR 1.45). The association of macrosomia was largely attenuated after adjustment for maternal BMI and lipids (OR 1.01, P=0.913). Using bidirectional mediation analysis, five candidate mediators (BMI, TG, HDL-C, LDL-C, and TG/HDL-C ratio) were identified as significant mediators in both directions. Moreover, hypertensive disorders showed the largest associations with LBW (PE β=-0.204; GH β=-0.067) in DML analyses. Evidence for a consistent causal effect of GDM on birth weight remains inconclusive. The observational association of macrosomia was largely explained by maternal metabolic status. The shared insulin-secretory biology more plausibly reflects genetic pleiotropy than a direct causal pathway. Hypertensive disorders showed stronger associations with birth weight reduction than GDM, supporting integrated management of glycemia, BMI, lipids and blood pressure.
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BibTeX
@article{li2026gestational,
title = {{Gestational Diabetes Mellitus and Birth Weight: A Bidirectional Mendelian Randomization and Cohort Study in China.}},
author = {Xia Li and Yue Peng and Yan Wang and Bin Yu},
journal = {Diabetes, metabolic syndrome and obesity : targets and therapy},
year = {2026},
month = nov,
doi = {10.2147/dmso.s653174},
url = {https://europepmc.org/article/MED/42999555},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Gestational Diabetes Mellitus and Birth Weight: A Bidirectional Mendelian Randomization and Cohort Study in China.
AU - Xia Li
AU - Yue Peng
AU - Yan Wang
AU - Bin Yu
PY - 2026
DA - 2026/11/03
JO - Diabetes, metabolic syndrome and obesity : targets and therapy
DO - 10.2147/dmso.s653174
UR - https://europepmc.org/article/MED/42999555
AB - Gestational diabetes mellitus (GDM) is regarded as a driver of fetal macrosomia, yet observational estimates of its effect on birth weight (BW) are vulnerable to confounding. Whether GDM causally shapes fetal growth, and through which shared biology, remains unresolved. We performed a bidirectional two-sample Mendelian randomization (MR) using FinnGen R11 GDM (16,802 cases) and the EGG Consortium birth-weight GWAS (n=286,868), with inverse-variance weighted (IVW, primary), MR-Egger, weighted median, weighted mode, RAPS estimators, MR-PRESSO and Bayesian colocalization. Multi-omics evidence (GSE92772, ST001948, INTERVAL cis-pQTLs) was integrated as hypothesis-generating evidence. In a cohort of 24,448 singleton pregnancies, linear and logistic regression, bootstrap mediation, and double/debiased machine learning (DML) were performed for verification. The primary IVW estimate for GDM to BW was null (β=-0.004, P=0.889) under extreme heterogeneity, and robust estimators showed nominally positive signals. Seven of 21 instruments flagged as outliers overlapping six colocalizing loci. Therefore, it is impossible to precluding a reliable causal interpretation. Reverse MR (BW to GDM) was exploratory (five instruments, all outliers). Colocalization identified six loci (CCND2, MTNR1B, GPSM1, ADCY5, CDKAL1, TCF7L2) with evidence of a shared causal variant (PP.H4≥0.5). All established islet beta-cell/insulin-secretion genes suggested shared upstream biology. In the cohort, GDM was associated with higher rates of macrosomia (OR 1.21) and lower birth weight (LBW, OR 1.45). The association of macrosomia was largely attenuated after adjustment for maternal BMI and lipids (OR 1.01, P=0.913). Using bidirectional mediation analysis, five candidate mediators (BMI, TG, HDL-C, LDL-C, and TG/HDL-C ratio) were identified as significant mediators in both directions. Moreover, hypertensive disorders showed the largest associations with LBW (PE β=-0.204; GH β=-0.067) in DML analyses. Evidence for a consistent causal effect of GDM on birth weight remains inconclusive. The observational association of macrosomia was largely explained by maternal metabolic status. The shared insulin-secretory biology more plausibly reflects genetic pleiotropy than a direct causal pathway. Hypertensive disorders showed stronger associations with birth weight reduction than GDM, supporting integrated management of glycemia, BMI, lipids and blood pressure.
SN - 1178-7007
ER -