Background: Mother’s genetic risk for type 2 diabetes (T2D) may influence intra-uterine glycemia leading to increased birth weight. However, the U-shaped relation between offspring birthweight and later-life T2D risk suggests that relations of offspring’s T2D genetic susceptibility with birthweight may be U-shaped.

Methods: We investigated the effects of maternal and offspring genetic risk for T2D on birthweight using genotype data from 949 mother-offspring pairs of African ancestry from the Hyperglycemia Adverse Pregnancy Outcome study. We generated a genetic risk score for T2D (dGRS) for mothers and offspring as the weighted sum of 90 T2D risk alleles. Offspring dGRS was separately calculated for birth weight-reducing and -increasing alleles based on the direction of correlation between a T2D-risk allele and birthweight in our data. We used linear regression adjusting for maternal and offspring covariates and the proportion of African ancestry to estimate the change in birthweight by quartiles of maternal and offspring dGRS.

Results: Changes in birthweight across increasing quartiles of mother’s dGRS were 0 (reference), 83.3g (95% CI: 6.7, 160.0), 102g (95% CI: 25.1, 179.5), and 92.9g (95% CI: 12.7, 173.1) (P-trend=0.042). In contrast, changes in birthweight across increasing quartiles of offspring dGRS based on birthweight-reducing alleles were 0, −105.7g (95% CI: −180.9, −30.5), −105.5g (95% CI: −180.4, −30.5), and −143.2g (95% CI: −218.6, −67.8) (P-trend=0.001), whereas those of dGRS based on birthweight-increasing alleles were 0, 15.3g (95% CI: −60.7, 91.3), 113.3g (95% CI: 38.1, 188.6), and 142.4g (95% CI: 66.8, 218.1) (P-trend=0.0002).

Conclusion: Maternal and offspring genetic risk for T2D exhibited a differential association with birth weight. Further characterization of individual alleles in a larger dataset will enhance our understanding of the causal roles of fetal and maternal genetic determinants of T2D on fetal growth.


M.L. Rahman: None. D. Shrestha: None. T. Workalemahu: None. J. Wu: None. C. Zhang: None. F. Tekola-Ayele: None.

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