Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun. 2022 May 2;13(1):2384. doi: 10.1038/s41467-022-30007-1.
Abnormal birthweight is associated with increased risk for cardiometabolic diseases in later life. Although the placenta is critical to fetal development and later life health, it has not been integrated into largescale functional genomics initiatives, and mechanisms of birthweight-associated variants identified by genome wide association studies (GWAS) are unclear. The goal of this study is to provide functional mechanistic insight into the causal pathway from a genetic variant to birthweight by integrating placental methylation and gene expression with established GWAS loci for birthweight. We identify placental DNA methylation and gene expression targets for several birthweight GWAS loci. The target genes are broadly enriched in cardiometabolic, immune response, and hormonal pathways. We find that methylation causally influences WNT3A, CTDNEP1, and RANBP2 expression in placenta. Multi-trait colocalization identifies PLEKHA1, FES, CTDNEP1, and PRMT7 as likely functional effector genes. These findings reveal candidate functional pathways that underpin the genetic regulation of birthweight via placental epigenetic and transcriptomic mechanisms. Clinical trial registration; ClinicalTrials.gov, NCT00912132.
出生体重异常与晚年患心血管代谢疾病的风险增加有关。尽管胎盘对胎儿发育和晚年健康至关重要，但它尚未纳入大规模的功能基因组学计划，并且全基因组关联研究（GWAS）确定的与出生体重相关的变异机制尚不清楚。本研究的目的是通过整合胎盘甲基化和基因表达与已建立的出生体重 GWAS 位点，为从遗传变异到出生体重的因果途径提供功能机制的见解。我们确定了几个与出生体重 GWAS 位点相关的胎盘 DNA 甲基化和基因表达靶标。靶基因广泛富集在心血管代谢、免疫反应和激素途径中。我们发现甲基化可导致胎盘 WNT3A、CTDNEP1 和 RANBP2 表达发生变化。多性状共定位将 PLEKHA1、FES、CTDNEP1 和 PRMT7 鉴定为可能的功能效应基因。这些发现揭示了候选功能途径，这些途径通过胎盘表观遗传和转录组机制为出生体重的遗传调控提供了基础。临床试验注册；ClinicalTrials.gov，NCT00912132。
