Placental multi-omics integration identifies candidate functional genes for birthweight

Fasil Tekola-Ayele (), Xuehuo Zeng, Suvo Chatterjee, Marion Ouidir, Corina Lesseur, Ke Hao, Jia Chen, Markos Tesfaye, Carmen J. Marsit, Tsegaselassie Workalemahu and Ronald Wapner
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Fasil Tekola-Ayele: National Institutes of Health
Xuehuo Zeng: National Institutes of Health
Suvo Chatterjee: National Institutes of Health
Marion Ouidir: National Institutes of Health
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 Institutes of Health
Carmen J. Marsit: Rollins School of Public Health of Emory University
Tsegaselassie Workalemahu: University of Utah
Ronald Wapner: Columbia University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30007-1

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