Replication of GWAS for Maternal Glycemia, Birthweight and their Interaction

描述（由申请方提供）：出生体重偏低和偏高是新生儿发病率和死亡率的主要原因，已确定出生体重与成人代谢性疾病风险之间存在相关性。胎儿的生长是由胎儿基因和母体子宫环境之间的相互作用决定的。我们正在进行一项全基因组关联研究（GWAS），以解决这一假设，即在母胎单位的背景下，基因-环境相互作用影响出生时的胎儿大小和母体代谢。这是通过使用从母亲和后代收集的高加索人，西班牙裔和非洲裔加勒比人DNA样本来完成的，作为NIH资助的Hyperlipidemia和不良妊娠结局（HAPO）研究的一部分。HAPO是一项多中心的国际研究，其中使用跨中心统一的标准化方案从25，000名不同种族背景的孕妇中收集了与胎儿生长和母体葡萄糖代谢相关的高质量表型数据。GWAS的具体目标是：（1）应用分析方法进行GWA绘图研究：（a）与出生时后代大小相关的定量表型，考虑胎龄、产次和母体体重等影响，以及（B）妊娠约28周时母体妊娠的测量，考虑母体体重、产次和年龄等影响。(2)研究母体基因、宫内环境和胎儿基因之间的相互作用，以确定调节出生时大小的相互作用和影响母体葡萄糖耐量的胎儿遗传变异。HAPO的一个优势是可用于复制研究的额外母亲和婴儿，其中表型数据是使用与初始GWAS中使用的相同的标准化和统一的方案收集的。鉴于外地住房储备金的预算有限，这项推广研究的具体目标是：（i）在来自HAPO群体的> 5，200名高加索母亲及其后代的独立队列中进行出生体重的第一阶段复制，和（ii）通过在另外的22个样本中对来自第1阶段的最显著SNP进行分型，来自两个英国队列的2000名母亲和后代。

DESCRIPTION (provided by applicant): Low and high birth weights are a major cause of neonatal morbidity and mortality, and an association between birth weight and risk of adult metabolic disease has been established. Fetal growth is determined by interactions between fetal genes and the maternal uterine environment. We are performing a genome wide association study (GWAS) to address the hypothesis that gene-environment interactions in the context of the maternal-fetal unit impact fetal size at birth and maternal metabolism. This is being accomplished using Caucasian, Hispanic, and Afro-Caribbean DNA samples collected from mothers and offspring as part of the NIH-funded Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO is a multicenter, international study in which high quality phenotypic data related to fetal growth and maternal glucose metabolism was collected from 25,000 pregnant women of varied racial backgrounds using standardized protocols that were uniform across centers. The specific aims for the GWAS are: (1) To apply analytic approaches for conducting GWA mapping studies on: (a) quantitative phenotypes related to offspring size at birth allowing for influences such as gestational age, parity and maternal weight, and (b) measures of maternal glycemia at ~28 weeks gestation allowing for influences such as maternal weight, parity and age. (2) To examine the interaction between maternal genes, the intrauterine environment, and fetal genes to identify interactions that modulate size at birth and fetal genetic variation that impacts on maternal glucose tolerance. A strength of HAPO is the additional mothers and babies available for replication studies in whom phenotype data was collected using standardized and uniform protocols identical to those used in the initial GWAS. Given the budgetary limitations of the RFA, the specific aims for this replication study are to: (i) perform a first stage of replication for birth weight in an independent cohort of >5,200 Caucasian mothers and their offspring from the HAPO population and (ii) to perform a second stage of replication for birth weight by typing the most significant SNPs from Stage 1 in an additional 22,000 mothers and offspring from two UK cohorts.