Genetic epidemiology of early growth and cardiometabolic diseases

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

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Abstract

Genetic epidemiology of early growth and links with cardiometabolic diseases Many cardiometabolic diseases in later life have links with early life growth. Advances in understanding the mechanism of early growth variation will provide early intervention opportunities for cardiometabolic outcomes. Dr. Tekola-Ayeles research aims to determine genetic mechanisms in early growth variations and links between early growth and cardiometabolic diseases/disparities in diverse ancestral populations. To achieve this goal, his group focuses on two overarching complementary research themes at the maternal-placental-fetal interface genetics of fetal growth and placental epigenome/transcriptome. The goal of the first research theme is to determine genetic influences on longitudinal fetal growth trajectories, the contribution of genetic ancestry to fetal growth differences, and the shared genetic architectures of fetal growth and cardiometabolic outcomes. Genome-wide single nucleotide polymorphism data have been generated from the NICHD Fetal Growth Studies, complemented by datasets obtained from consortia-based genetic databases and the NIH Database of Genotypes and Phenotypes. This project yielded the following key insights: (1) identified novel maternal genetic loci that influence fetal weight at specific in-utero time periods (PMC7252673), elucidated that fetal genetic influences on fetal growth differ based on gestational age (PMC5940684) and ancestry (PMC5967042), and (2) built evidence that genetic mechanisms partly explain the links between maternal cardiometabolic risk, fetal growth, and future risk for cardiometabolic diseases (PMC6411883, PMC6449964, PMC6753636, PMC6592626, PMC6885118, PMC6224338, PMC7794220). Further, a recently completed pilot study examined the potential to obtain usable DNA for genotyping banked serum samples from the Collaborative Perinatal Project (CPP). By providing proof-of-principle, the pilot paves the way for linking genetic data with the detailed phenotypic records of the CPP to address high impact long-standing biological questions in early growth, childhood adiposity and subsequent cardiometabolic health. The goal of the second research theme is to investigate the role of placental genetic/epigenetic/transcriptomic mechanisms and the aging clock of the placenta in fetal growth and related maternal cardiometabolic factors. Key findings of this project include the following: (1) demonstrated that epigenetic aging of the placenta has sexually dimorphic relationships with fetal growth (PMC6710059) and significant associations with maternal cardiometabolic factors and genetic ancestry (PMC6691987), and (2) identified novel placental DNA methylation and transcriptomic signatures for birthweight and maternal cardiometabolic factors, including loci that suggest placental DNA methylation changes as early mechanisms underlying subsequent cardiometabolic disease risk (PMC7261634, PMC7122078, PMC7466909, PMC7268466, PMC7371466). A study of genetic and environmental influences on placental DNA methylation variation revealed that gene-environment interactions account for more than 80% placental variable DNA methylation, and led to a new resource of Variable Methylation Region for placenta (PMID: 34155504). Dr. Tekola-Ayele has initiated a new genetic study within SPAN: 1) to identify fetal genetic factors that regulate fetal growth and the aging clock of the placenta and through discovery in African Americans followed by trans-ethnic meta-analysis, and 2) to investigate genetic, epigenetic and transcriptomic mechanisms in placental regulation of fetal growth.