Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.

Anshuman Sewda,Laura E Mitchell,Fadi Musfee,A J Agopian,Deanne Taylor,Bernice E Morrow,Elizabeth Goldmuntz,Hakon Hakonarson,On Behalf Of The Pediatric Cardiac Genomics Consortium

doi:10.1371/journal.pone.0234357

Abstract

Congenital heart defects (CHDs) affect approximately 1% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.

Highlights

Congenital heart defects (CHDs) are the most common group of birth defects, with a prevalence of approximately 1% in live births [1]
As for many birth defects, the risk of CHDs is associated with several genetically-mediated, maternal phenotypes, including folate status, obesity, pregestational diabetes, chronic hypertension, and preeclampsia [4, 5]
Patients with conotruncal heart defects (CTDs) and their parents were recruited through the Cardiac Center at Children’s Hospital of Philadelphia (CHOP) (1992–2010), under a protocol approved by the Institutional Review Board for the Protection of Human Subjects at CHOP [14, 15]

Summary

Introduction

Congenital heart defects (CHDs) are the most common group of birth defects, with a prevalence of approximately 1% in live births [1]. As for many birth defects, the risk of CHDs is associated with several genetically-mediated, maternal phenotypes, including folate status, obesity, pregestational diabetes, chronic hypertension, and preeclampsia [4, 5]. The genotype data used in these studies are available at: Pediatric Cardiac Genomics Consortium: https://www.ncbi.nlm.nih. Gov/projects/gap/cgi-bin/study.cgi?study_id= phs001194.v2.p2 CHOP pediatric controls: https:// www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study. The genotype data used in these studies are available at: Pediatric Cardiac Genomics Consortium: https://www.ncbi.nlm.nih. gov/projects/gap/cgi-bin/study.cgi?study_id= phs001194.v2.p2 CHOP pediatric controls: https:// www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study. cgi?study_id=phs000490.v1.p1 CHOP CTD trios: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/ study.cgi?study_id=phs000881.v1.p1

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Results

Conclusion