Replication of GWAS for Maternal Glycemia, Birthweight and their Interaction

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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.