Genetic epidemiology of early growth and cardiometabolic diseases

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications & trials

Abstract

Aberrant fetal growth is known to be a risk factor for cardiometabolic diseases in later life; however, the mechanisms that underlies the links between early growth and later life cardiometabolic diseases are not well understood. Fetal growth also exhibits significant differences among individuals and populations; what underlies population differences in fetal growth and consequent cardiometabolic outcomes has remained puzzling because environmental factors explain only a small proportion of these differences. Insights into the biological pathways shared between phenotypes of early growth and adult cardiometabolic outcomes will facilitate development of interventions that benefit health across the life course. Ongoing studies aim to address the following research questions: Investigate genetic mechanisms in longitudinal fetal growth variations and the contribution of genetic ancestry for fetal growth differences among populations. This study is conducted using genome-wide genotype data generated from stored biospecimens collected by the NICHD Fetal Growth Studies, multi-ethnic study of fetal growth as well as other resources. The goal of the study is to unravel maternal-placental-fetal genetic and epigenetic factors (including genetic ancestry, cardiometabolic disease genetic risk, and epigenetic/transcriptomic signatures) that influence fetal growth in diverse populations. In a study of twin gestations from the NICHD Fetal Growth Studies cohort, we found that the influence of genetic factors steadily increases with gestational age compared to environmental influences that showed the highest influence during early gestation. The study also demonstrated that the genetic influence on fetal weight peaks at the end of second trimester of pregnancy (PMID: 29740100). In another study that compared the cumulative burden of genetic loci known to be associated with birthweight among ancestrally diverse global populations, we found ancestral differences in the burden of the birthweight-reducing loci (PMID: 29792231). In addition, a study has found fetal sex-dependent influence of epigenetic age acceleration of the placenta on fetal growth (PMID: 31395791). The team is currently undertaking analyses of genetic, epigenetic, and transcriptomic data to identify maternal genetic loci that influence longitudinal fetal growth; determine the contributions of maternal genetic ancestry and cardiometabolic genetic factors to individual and population difference in fetal growth; and identify placental transcriptomic/epigenetic signatures of maternal dyslipidemia, obesity, and blood pressure. Identify shared genetic pathways between birth weight and adult cardiometabolic outcomes, and understand the influence of maternal metabolic genetic factors on offspring birth outcomes. This study examines the extent of pleiotropy and enrichment of biologically functional loci using large-scale genome-wide association study genotype data contributed by several consortia as well as the database of Genotypes and Phenotypes (www.ncbi.nlm.nih.gov/gap). The study found high degree of shared genetic influences and identified novel loci that jointly influence birthweight and adult coronary artery disease and obesity traits (PMID: 30858448). Evaluate the potential to obtain DNA of high quality from sources other than whole blood. The long-term goal of this project is to leverage existing large-scale population biobanks in future genetic-epidemiology studies of early growth-cardiometabolic links. A pilot study has been designed to evaluate whether stored serum can yield sufficient DNA that is usable for future genomic research using banked serum samples from the Collaborative Perinatal Project, a national pregnancy cohort of more than 48,000 women and their offspring enrolled between the years 1959 and 1966. The pilot phase experiment is underway.