PDF(Pubmed)
Abstract：
BACKGROUND: Maternal genetic risk of type 2 diabetes (T2D) has been associated with fetal growth, but the influence of genetic ancestry is not yet fully understood. We aimed to investigate the influence of genetic distance (GD) and genetic ancestry proportion (GAP) on the association of maternal genetic risk score of T2D (GRST2D) with fetal weight and birthweight.
METHODS: Multi-ancestral pregnant women (n = 1,837) from the NICHD Fetal Growth Studies - Singletons cohort were included in the current analyses. Fetal weight (in grams, g) was estimated from ultrasound measurements of fetal biometry, and birthweight (g) was measured at delivery. GRST2D was calculated using T2D-associated variants identified in the latest trans-ancestral genome-wide association study and was categorized into quartiles. GD and GAP were estimated using genotype data of four reference populations. GD was categorized into closest, middle, and farthest tertiles, and GAP was categorized as highest, medium, and lowest. Linear regression analyses were performed to test the association of GRST2D with fetal weight and birthweight, adjusted for covariates, in each GD and GAP category.
RESULTS: Among women with the closest GD from African and Amerindigenous ancestries, the fourth and third GRST2D quartile was significantly associated with 5.18 to 7.48 g (weeks 17-20) and 6.83 to 25.44 g (weeks 19-27) larger fetal weight compared to the first quartile, respectively. Among women with middle GD from European ancestry, the fourth GRST2D quartile was significantly associated with 5.73 to 21.21 g (weeks 18-26) larger fetal weight. Furthermore, among women with middle GD from European and African ancestries, the fourth and second GRST2D quartiles were significantly associated with 117.04 g (95% CI = 23.88-210.20, p = 0.014) and 95.05 g (95% CI = 4.73-185.36, p = 0.039) larger birthweight compared to the first quartile, respectively. The absence of significant association among women with the closest GD from East Asian ancestry was complemented by a positive significant association among women with the highest East Asian GAP.
CONCLUSIONS: The association between maternal GRST2D and fetal growth began in early-second trimester and was influenced by GD and GAP. The results suggest the use of genetic GD and GAP could improve the generalizability of GRS.
METHODS: Multi-ancestral pregnant women (n = 1,837) from the NICHD Fetal Growth Studies - Singletons cohort were included in the current analyses. Fetal weight (in grams, g) was estimated from ultrasound measurements of fetal biometry, and birthweight (g) was measured at delivery. GRST2D was calculated using T2D-associated variants identified in the latest trans-ancestral genome-wide association study and was categorized into quartiles. GD and GAP were estimated using genotype data of four reference populations. GD was categorized into closest, middle, and farthest tertiles, and GAP was categorized as highest, medium, and lowest. Linear regression analyses were performed to test the association of GRST2D with fetal weight and birthweight, adjusted for covariates, in each GD and GAP category.
RESULTS: Among women with the closest GD from African and Amerindigenous ancestries, the fourth and third GRST2D quartile was significantly associated with 5.18 to 7.48 g (weeks 17-20) and 6.83 to 25.44 g (weeks 19-27) larger fetal weight compared to the first quartile, respectively. Among women with middle GD from European ancestry, the fourth GRST2D quartile was significantly associated with 5.73 to 21.21 g (weeks 18-26) larger fetal weight. Furthermore, among women with middle GD from European and African ancestries, the fourth and second GRST2D quartiles were significantly associated with 117.04 g (95% CI = 23.88-210.20, p = 0.014) and 95.05 g (95% CI = 4.73-185.36, p = 0.039) larger birthweight compared to the first quartile, respectively. The absence of significant association among women with the closest GD from East Asian ancestry was complemented by a positive significant association among women with the highest East Asian GAP.
CONCLUSIONS: The association between maternal GRST2D and fetal growth began in early-second trimester and was influenced by GD and GAP. The results suggest the use of genetic GD and GAP could improve the generalizability of GRS.
摘要：
背景：2型糖尿病（T2D）的母体遗传风险与胎儿生长有关，但是遗传祖先的影响还没有完全理解。我们旨在研究遗传距离（GD）和遗传血统比例（GAP）对T2D的母体遗传风险评分（GRST2D）与胎儿体重和出生体重的相关性的影响。
方法：来自NICHD胎儿生长研究的多祖先孕妇（n=1,837）——单胎队列被纳入当前分析。胎儿体重(以克计，g)是根据胎儿生物测定的超声测量结果估计的，分娩时测量出生体重(g)。使用最新的跨祖先全基因组关联研究中鉴定的T2D相关变体计算GRST2D，并将其分类为四分位数。使用四个参考人群的基因型数据估计GD和GAP。GD被归类为最接近的，中间,和最远的三元，GAP被归类为最高，中等,和最低。进行线性回归分析以测试GRST2D与胎儿体重和出生体重的关联。对协变量进行调整，在每个GD和GAP类别中。
结果：在来自非洲和美洲土著祖先的GD最接近的女性中，与第一个四分位数相比，第四个和第三个GRST2D四分位数与5.18至7.48g（17-20周）和6.83至25.44g（19-27周）的胎儿体重显着相关，分别。在来自欧洲血统的中GD女性中，第4个GRST2D四分位数与5.73~21.21g(18~26周)更大的胎儿体重显著相关.此外，在来自欧洲和非洲祖先的中间GD的女性中，与第一个四分位数相比，第四个和第二个GRST2D四分位数与117.04g（95％CI=23.88-210.20，p=0.014）和95.05g（95％CI=4.73-185.36，p=0.039）更大的出生体重显着相关，分别。与东亚血统最接近GD的女性之间没有显着关联，而与东亚GAP最高的女性之间存在正显著关联。
结论：母体GRST2D与胎儿生长之间的关联始于孕中期早期，并受GD和GAP的影响。结果表明，遗传GD和GAP的使用可以提高GRS的普适性。
方法：来自NICHD胎儿生长研究的多祖先孕妇（n=1,837）——单胎队列被纳入当前分析。胎儿体重(以克计，g)是根据胎儿生物测定的超声测量结果估计的，分娩时测量出生体重(g)。使用最新的跨祖先全基因组关联研究中鉴定的T2D相关变体计算GRST2D，并将其分类为四分位数。使用四个参考人群的基因型数据估计GD和GAP。GD被归类为最接近的，中间,和最远的三元，GAP被归类为最高，中等,和最低。进行线性回归分析以测试GRST2D与胎儿体重和出生体重的关联。对协变量进行调整，在每个GD和GAP类别中。
结果：在来自非洲和美洲土著祖先的GD最接近的女性中，与第一个四分位数相比，第四个和第三个GRST2D四分位数与5.18至7.48g（17-20周）和6.83至25.44g（19-27周）的胎儿体重显着相关，分别。在来自欧洲血统的中GD女性中，第4个GRST2D四分位数与5.73~21.21g(18~26周)更大的胎儿体重显著相关.此外，在来自欧洲和非洲祖先的中间GD的女性中，与第一个四分位数相比，第四个和第二个GRST2D四分位数与117.04g（95％CI=23.88-210.20，p=0.014）和95.05g（95％CI=4.73-185.36，p=0.039）更大的出生体重显着相关，分别。与东亚血统最接近GD的女性之间没有显着关联，而与东亚GAP最高的女性之间存在正显著关联。
结论：母体GRST2D与胎儿生长之间的关联始于孕中期早期，并受GD和GAP的影响。结果表明，遗传GD和GAP的使用可以提高GRS的普适性。
