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Associations between maternal gestational diabetes mellitus and offspring cerebral palsy: a two-sample Mendelian
Honghao Peng1, Yun Shu2, Siyu Lu1
1Department of Pediatrics, Second Affiliated Hospital of the Army Medical University, Chongqing, China.
Insights
Gestational diabetes mellitus (GDM) in pregnancy is causally linked to an increased risk of cerebral palsy (CP) in offspring. This study found no evidence of a link between GDM and autism spectrum disorders (ASD) or epilepsy (EP).
Area of Science:
- Genetics and Epidemiology
- Maternal and Child Health
- Neurology
Background:
- Observational studies show mixed results on the association between gestational diabetes mellitus (GDM) and pediatric neurological disorders (PNDs) like cerebral palsy (CP), autism spectrum disorders (ASD), and epilepsy (EP).
- The unclear causal link between GDM and PNDs necessitates further investigation for effective prenatal interventions.
- This study aims to clarify the causal relationship between GDM and offspring PNDs using a robust genetic approach.
Purpose of the Study:
- To investigate the potential causal effect of gestational diabetes mellitus (GDM) on the risk of developing cerebral palsy (CP), autism spectrum disorders (ASD), and epilepsy (EP) in offspring.
- To leverage a two-sample Mendelian randomization (MR) approach to overcome limitations of observational studies and establish causality.
- To inform the development of targeted interventions during pregnancy to reduce the risk of PNDs.
Main Methods:
- Employed a two-sample Mendelian randomization (MR) design utilizing 6 single nucleotide polymorphisms (SNPs) strongly associated with GDM.
- Obtained summary-level genetic data for CP, ASD, and EP from large-scale Genome-Wide Association Studies (GWAS) via the IEU Open GWAS project.
- Applied the inverse variance-weighted (IVW) method for primary analysis and conducted sensitivity analyses to ensure result robustness and assess pleiotropy.
Main Results:
- The study found a significant association between genetically predicted GDM and an increased risk of offspring cerebral palsy (CP) (OR: 1.74, 95% CI: 1.27-2.37, P<0.001).
- No statistically significant causal relationship was detected between GDM and the risk of autism spectrum disorders (ASD) or epilepsy (EP).
- Sensitivity analyses confirmed the primary findings, and MR-Egger regression indicated no significant horizontal pleiotropy (P=0.48).
Conclusions:
- This Mendelian randomization study provides strong evidence for a causal link between GDM and an elevated risk of cerebral palsy in offspring.
- The findings suggest that GDM is not causally associated with an increased risk of autism spectrum disorders or epilepsy in children.
- These results highlight the importance of managing GDM during pregnancy to potentially mitigate the risk of CP in newborns.
Background:
Observational studies on the association between gestational diabetes mellitus (GDM) during pregnancy and pediatric neurological disorders (PNDs) such as cerebral palsy (CP), autism spectrum disorders (ASD), and epilepsy (EP) in offspring have yielded mixed findings, creating ambiguity in causal interpretations. The direct link between GDM and these PNDs remains unclear. Elucidating this connection is vital for developing effective early intervention strategies during pregnancy to mitigate the risk of PNDs in the offspring. This study utilizes a two-sample (2-sample) Mendelian randomization (MR) approach to investigate the causal relationship between GDM and its impact on CP, ASD, and EP in offspring.
Methods:
We employed 2-sample MR using 6 single nucleotide polymorphisms (SNPs) strongly associated with GDM. Summary-level data for CP, ASD, and EP were obtained from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) project, encompassing sample sizes of 217,278, 46,351, and 463,010, respectively. The robustness of our findings was assessed using the inverse variance-weighted (IVW) method along with additional sensitivity analyses.
Results:
The results demonstrate that GDM is associated with a higher risk of offspring CP as determined by the IVW method [odds ratio (OR): 1.74; 95% confidence interval (CI): 1.27-2.37; P<0.001]. In contrast, no association was observed between GDM and ASD or EP. Additionally, alternative methods for sensitivity analyses showed consistent results, and there was no pleiotropy detected using MR-Egger regression (P=0.48).
Conclusions:
This study provides strong evidence supporting a positive causal relationship between genetically predicted GDM and the increased risk of offspring CP, with no observed correlation found with ASD or EP.
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