In-utero exposure to maternal diabetes and DNA methylation alterations in the Next Generation birth cohort
Why this work is in the frame
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Bibliographic record
Abstract
INTRODUCTION: The incidence of type 2 diabetes (T2D) in youth is increasing and in-utero exposure to maternal diabetes is a known risk factor, with higher risk associated with pregestational T2D exposure compared to gestational diabetes mellitus (GDM) exposure. We hypothesize this differential risk is reflected in DNA methylation (DNAm) changes induced by differential timing of in-utero exposure to maternal diabetes, and that exposure to diabetes throughout pregnancy (T2D) compared to exposure later in development (GDM), induces different DNAm signatures and different T2D risk to offspring. This study presents an epigenome-wide investigation of DNAm alterations associated with in-utero exposure to either maternal pregestational T2D or GDM, to determine if the timing of prenatal diabetes exposure differentially alters DNAm. METHODS: We performed an epigenome-wide analysis on cord blood from 99 newborns exposed to pregestational T2D, 70 newborns exposed to GDM, and 41 unexposed to diabetes in-utero from the Next Generation birth cohort. Associations were tested using multiple linear regression models while adjusting for sex, maternal age, BMI, smoking status, gestational age, cord blood cell type proportions and batch effects. RESULTS: We identified 27 differentially methylated sites associated with exposure to GDM, 27 sites associated with exposure to T2D, and 9 common sites associated with exposure to either GDM or T2D (adjusted p value < 0.05 and effect size estimate > 0.01). One site at CLDN15 and two unannotated sites were previously reported as associated with obesity. We also identified 87 differentially methylated regions (DMRs) associated with in-utero exposure to GDM and 69 DMRs associated with in-utero exposure to T2D. We identified 23 DMR sites that were previously associated with obesity, three with T2D and five with in-utero exposure to GDM. Furthermore, we identified six CpG sites in the PTPRN2 gene, a gene previously associated with DNAm differences in blood of youth with T2D from the same population. CONCLUSION: Our findings support that in-utero exposure to maternal diabetes is associated with DNAm alterations in offspring. Moreover, the timing of maternal diabetes in-utero exposure (GDM or T2D) produces overlapping but distinct DNAm patterns, suggesting that the window of exposure to maternal diabetes produces different molecular modifications and may reflect, at least in part, the difference in risk for youth-onset T2D in offspring. We also identified sites in this study that have been previously associated with T2D or obesity, which may serve as potential early-life biomarkers of exposure and/or risk, warranting further investigation in longitudinal studies.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it