Ancestry-Matched and Cross-Ancestry Genetic Risk Scores of Type 2 Diabetes in Pregnant Women and Fetal Growth: A Study in an Ancestrally Diverse Cohort

Abstract

Maternal genetic variants associated with offspring birth weight and adult type 2 diabetes (T2D) risk loci show some overlap. Whether T2D genetic risk influences longitudinal fetal weight and the gestational timing when these relationships begin is unknown. We investigated the associations of T2D genetic risk scores (GRS) with longitudinal fetal weight and birth weight among 1,513 pregnant women from four ancestral groups. Women had up to five ultrasonography examinations. Ancestry-matched GRS were constructed separately using 380 European- (GRSeur), 104 African- (GRSafr), and 189 East Asian- (GRSeas) related T2D loci discovered in different population groups. Among European Americans, the highest quartile GRSeur was significantly associated with 53.8 g higher fetal weight (95% CI 19.2-88.5) over the pregnancy. The associations began at gestational week 24 and continued through week 40, with a 106.8 g (95% CI 6.5-207.1) increase in birth weight. The findings were similar in analysis further adjusted for maternal glucose challenge test results. No consistent association was found using ancestry-matched or cross-ancestry GRS in non-Europeans. In conclusion, T2D genetic susceptibility may influence fetal growth starting at midsecond trimester among Europeans. Absence of similar associations in non-Europeans urges the need for further genetic T2D studies in diverse ancestries.

Trial registration: ClinicalTrials.gov NCT00912132.

© 2022 by the American Diabetes Association.

Figures

Figure 1

Changes in longitudinal fetal weight (in grams) for quartile increase in ancestry-matched GRS-related T2D (N = 1,513 from the NICHD Fetal Growth Studies–Singleton cohort). Adjusted for prepregnancy BMI, offspring sex, gestational age at measurements, and for the first five genetic PCs. Dots indicate the estimates, vertical lines indicate the 95% CIs, and horizontal lines indicate the null.

Figure 2

Weekly change in estimated fetal weight (in grams) for quartile increase in GRSeur-related T2D among European American women (A), and GRSeas-related T2D among East Asian American women (B) (N = 1,513 from the NICHD Fetal Growth Studies–Singleton cohort). Adjusted for maternal age, prepregnancy BMI, offspring sex, and for the first five genetic PCs. Black curved lines indicate the estimates, gray zones indicate the 95% CIs, and the horizontal lines indicate the null.

Figure 3

Change in birth weight (in grams) for quartile increase in ancestry-matched GRS-related T2D (N = 1,513 from the NICHD Fetal Growth Studies–Singleton cohort). Adjusted for maternal age, prepregnancy BMI, offspring sex, gestational age at delivery, and for the first five genetic PCs. Dots indicate the estimates, vertical lines indicate the 95% CIs, and horizontal lines indicate the null.