TY - JOUR
T1 - Placental multi-omics integration identifies candidate functional genes for birthweight
AU - Tekola-Ayele, Fasil
AU - Zeng, Xuehuo
AU - Chatterjee, Suvo
AU - Ouidir, Marion
AU - Lesseur, Corina
AU - Hao, Ke
AU - Chen, Jia
AU - Tesfaye, Markos
AU - Marsit, Carmen J.
AU - Workalemahu, Tsegaselassie
AU - Wapner, Ronald
N1 - Funding Information:
This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) including American Recovery and Reinvestment Act funding via contract numbers HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C and HHSN27500008. Additional support was obtained from the NIH Office of the Director, the National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). RICHS is partially supported by NIH-NIEHS R01ES022223 (CJM, JC and KH), NIH-NIEHS R01ES022223-03S1 (CJM), and NIH-NIEHS R24ES028507 (CJM). CL is funded through NIH-NICHD R00HD097286. The authors acknowledge the research teams at all participating clinical centers for the NICHD Fetal Growth Studies, including Christina Care Health Systems, Columbia University, Fountain Valley Hospital, California, Long Beach Memorial Medical Center, New York Hospital, Queens, Northwestern University, University of Alabama at Birmingham, University of California, Irvine, Medical University of South Carolina, Saint Peters University Hospital, Tufts University, and Women and Infants Hospital of Rhode Island. The authors also acknowledge C-TASC and The EMMES Corporations in providing data and imaging support. Genotyping was performed in the Department of Laboratory Medicine and Pathology, University of Minnesota. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov ). The authors are also thankful to the RICHS study participants for their participation, and the study staff at Women and Infants Hospital for their dedication to the project. Data on birthweight GWAS summary statistics have been contributed by the EGG Consortium using the UK Biobank Resource and has been downloaded from www.egg-consortium.org.
Funding Information:
This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) including American Recovery and Reinvestment Act funding via contract numbers HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C and HHSN27500008. Additional support was obtained from the NIH Office of the Director, the National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). RICHS is partially supported by NIH-NIEHS R01ES022223 (CJM, JC and KH), NIH-NIEHS R01ES022223-03S1 (CJM), and NIH-NIEHS R24ES028507 (CJM). CL is funded through NIH-NICHD R00HD097286. The authors acknowledge the research teams at all participating clinical centers for the NICHD Fetal Growth Studies, including Christina Care Health Systems, Columbia University, Fountain Valley Hospital, California, Long Beach Memorial Medical Center, New York Hospital, Queens, Northwestern University, University of Alabama at Birmingham, University of California, Irvine, Medical University of South Carolina, Saint Peters University Hospital, Tufts University, and Women and Infants Hospital of Rhode Island. The authors also acknowledge C-TASC and The EMMES Corporations in providing data and imaging support. Genotyping was performed in the Department of Laboratory Medicine and Pathology, University of Minnesota. This work utilized the computational resources of the NIH HPC Biowulf cluster ( http://hpc.nih.gov ). The authors are also thankful to the RICHS study participants for their participation, and the study staff at Women and Infants Hospital for their dedication to the project. Data on birthweight GWAS summary statistics have been contributed by the EGG Consortium using the UK Biobank Resource and has been downloaded from www.egg-consortium.org .
Funding Information:
Open Access funding provided by the National Institutes of Health (NIH).
Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85129283027&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-30007-1
DO - 10.1038/s41467-022-30007-1
M3 - Article
C2 - 35501330
AN - SCOPUS:85129283027
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2384
ER -