Genetic epidemiology of early growth and cardiometabolic diseases

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications & trials

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. 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 applied an innovative multi-omics approach in placenta to address whether genetic variants identified in GWAS of birthweight regulate placental epigenome and transcriptome, and to identify candidate causal functional genes, which is a major gap in the post-GWAS field. In a successful intramural-extramural collaboration led by Dr. Tekola-Ayele, it has been found that an overwhelmingly significant proportion of fetal genetic variants previously known to be associated with birthweight also regulate placental gene expression and methylation levels in their vicinity. The identified target genes have been found to be broadly enriched for hormonal, immune response and cardiometabolic pathways, and key high-priority functional/causal genes have been identified as key targets for future functional experiments and translational studies (Nat Commun 2022;13(1):2384; PMID: 35501330). In another study, the team fuond that placentas of male and female small-for-gestational-age (SGA) infants differed in their gene expression profile. Whereas differentially expressed genes in male SGA were enriched for immune signaling, differentially expressed genes in female SGA were enriched for organ development. The study demonstrated that SGA pathogenesis is best elucidated by treating sex as a biological variable (Placenta 2022;121:82-90; PMID: 35303517). Novel placental DNA methylation sites linked to maternal depression have also been identified. Some of the methylation changes are near/within genes known to be associated with fetal brain development and neuropsychiatric diseases in later life, suggesting the early placental molecular embedding of later-onset chronic diseases(Epigenomics 2021;13:1485-1496; PMID: 34585950). In a study investigating the link between maternal polygenic risk score of type 2 diabetes and fetal growth, the earliest gestational week in which maternal diabetes-related genetic effects on fetal weight has been identified in European-ancestry women, but not in other ancestral population groups. Absence of cross-ancestral utility of polygenic risk of diabetes in diverse ancestral populations elucidated the need for expanding genomic studies of diabetes in diverse ancestral populations to ensure broad biomedical and clinical utility (Diabetes 2022;71:340-349; PMID: 34789498). 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.