DESCRIPTION (provided by applicant): Newborns with high or low body fat at birth have an increased susceptibility to poor metabolic and/or cardiovascular health in childhood and adulthood. Unlike adult adiposity which is present in essentially all mammals, significant fat mass at birth is unique to humans among primates and mammals more generally, suggesting a recently evolved genetic component. Fat accretion during development is modulated by maternal metabolic factors (e.g., glucose and triglycerides), but we have now determined that genetic factors also contribute to newborn human adiposity at birth. In a genome wide association study performed in a multi-ethnic cohort of newborns whose mothers underwent glucose testing during gestation we identified a locus on chromosome 3, 3q25.31, which exhibits association in multiple race groups with measures of newborn adiposity. The associated region is intergenic, and we are proposing to identify genetic variation within the locus to address the hypothesis that genetic variants within 3q25.31 affect the expression of long noncoding RNAs present in the locus. We will address this hypothesis by performing the following specific aims using DNA and phenotype data collected as part of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study. Aim 1: To use targeted genomic capture and next generation sequencing to identify additional common, low frequency and rare variants within 3q25.31 in a total of 800 newborns of Northern European, Afro-Caribbean, Mexican-American and Thai ancestry in the upper and lower 10th percentiles for sum of skinfolds, a measure newborn adiposity. Aim 2: To use high throughput approaches to define the impact of variants on gene expression and expression of lncRNAs within the chromosome 3 locus. Aim 3: To use comparative genomic approaches to define the underlying genetic architecture and function of the chromosome 3 locus in humans compared to other non-human primates. Aim 4: To demonstrate that variants which have a functional impact are associated with measures of newborn adiposity by genotyping the identified SNPs in up to 10,900 additional HAPO newborns from the four race groups. Accomplishing these aims will provide fundamental new insight into genetic factors regulating newborn anthropometric traits. This will have important implications for fetal outcomes, long-term health of the newborn, and evolution of unique human traits important for the support of neonatal brain growth.

PUBLIC HEALTH RELEVANCE: Newborns with high or low fat at birth have an increased susceptibility to poor metabolic and heart health. Maternal metabolic factors (e.g., glucose levels) modulate fetal fat accumulation, but we have now identified a chromosomal locus associated with fetal fat accumulation in multiple race groups, suggesting that genetic factors are also important. We believe that this chromosomal locus affects fetal fat accumulation by regulating the expression of genes important for fat accumulation, so the goal of this study is to identify the genetic variation within this chromosomal locus important for regulating gene expression to help define the mechanism by which variation in newborn fat impacts childhood and adult metabolic and heart health.