Placental multi-omics integration identifies candidate functional genes for birthweight

• Type of Material: Article
• Authors: Fasil Tekola-Ayele, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Xuehuo Zeng, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Suvo Chatterjee, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Marion Ouidir, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Corina Lesseur, Icahn School of Medicine at Mount Sinai; Ke Hao, Icahn School of Medicine at Mount Sinai; Jia Chen, Icahn School of Medicine at Mount Sinai; Markos Tesfaye, National Institute on Alcohol Abuse and Alcoholism & National Institute of Nursing Research; Carmen Marsit, Emory University; Tsegaselassie Workalemahu, University of Utah; Ronald Wapner, Columbia University
• Language: English
• Date: 2022-05-02
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-30007-1
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 2384
• End Page: 2384
• Grant/Funding Information: Open Access funding provided by the National Institutes of Health (NIH).
• Keywords: INTERFACE; CELL; Multidisciplinary Sciences; GENOME-WIDE ASSOCIATION; VARIANTS; RISK; Science & Technology - Other Topics; Science & Technology; RELEVANCE; LOCI; FETAL-GROWTH; ARGININE METHYLATION; INFANT
• Research Categories: Health Sciences, Obstetrics and Gynecology

Abstract

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.