Genetics of early childhood longitudinal growth and obesity among African- and European- Americans in the Collaborative Perinatal Project

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Abstract

Identifying genetic factors that influence early childhood growth- and obesity-related phenotypes can inform the etiology of obesity and strategies to prevent and treat childhood and adult cardiometabolic diseases. However, the genetic factors that influence early childhood growth- and obesity-related phenotypes are not well understood, particularly in non-European ancestry populations with disproportionately high burden of childhood obesity and its health consequences. To date, there is no GWAS of early childhood growth- and obesity-related phenotypes involving diverse ancestries and multiple early childhood ages with longitudinally measured anthropometry. Absence of GWAS in non-European populations hinders opportunities for discovering additional genetic factors, identifying causal loci even among known loci, cross-ancestral transferability of risk loci, and equitable clinical translation. To address the data gap in genetics of early childhood growth- and obesity-related traits based on well-powered ancestrally diverse and longitudinal cohorts, this project will identify genetic factors associated with childhood growth and obesity traits in African and European ancestry individuals using data from the Collaborative Perinatal Project (CPP). The CPP is a prospective pregnancy cohort that enrolled 48197 pregnant women (46% White, 46.2% African American, 6.8% Puerto Rican, 1% others) who had prenatal care at 12 medical centers in the United States in 1959-1965. Women were followed from early pregnancy onwards and their offspring were monitored at seven serial times from birth through early school ages of 4, 8, and 12 months and 3, 4, and 7 years. Detailed physical growth measurements and neurodevelopmental assessments were performed at the child follow-up visits. Serum was isolated from whole blood samples of women, cord blood of newborns, and whole blood of selected abnormal offspring obtained at their 4-month pediatric examination. In this project, which followed a successful pilot demonstrating that the stored CPP samples can be used for genomics research, DNA will be isolated from cordblood serum and whole genome genotyping of DNA samples will be performed using Genome-wide Arrays designed for diverse ancestral populations. Genotyping is planed to be completed in the next 2 years. Significance of this project includes the following: (1) The CPP cohort lends opportunities to discover novel genetic loci among Africans and Europeans and improve functional characterization of known loci discovered in European populations. Trans-ethnic approaches facilitate identifying causal loci and functional genes. Our study will facilitate efforts to determine early origins of adult diseases and paves pathways for interventions by determining genetic effects that are distinct to some developmental timings and those that are sustained across ages. (2) Children in the CPP era did not face present-day environmental risk factors for metabolic conditions such as obesity. This offers a unique avenue to separate factors that require both a genetic and an environmental component from those that are entirely genetic. This potential interaction between genetic factors discovered via the CPP and recent environmental modifiers can be evaluated using other recent cohorts. (3) Genomics research in African Americans is rare and genetic loci identified in GWAS involving Europeans may not translate to African Americans. Under-representation of non-European populations in genomics research not only misses the opportunity to understand the genetic basis of diseases, but can also contribute to health inequities in genomics-informed health care in the future. Our study can contribute to informing the pathophysiology of childhood growth and obesity in African Americans and how it interacts with non-genetic factors, shedding light on molecular mechanisms of childhood obesity burden. (4) Establishing a genomic resource in the CPP can serve a broad scientific community and address a spectrum of research questions. The project will establish a large genomic resource that offers opportunities for the scientific community to test several hypotheses in African and European ancestry populations. Our genetic data can be shared (integrated with) future follow-up studies of CPP children in adulthood, to offer relevant biological links between early childhood growth/obesity and later life chronic cardiometabolic diseases.