Identifying Genes Associated with Obstructive Congenital Heart Defects Using a Family-Based Genetic Random Field Method: Results from the National Birth Defects Prevention Study

Manyan Huang; Nianjun Liu; Stephanie M Ware; John S Witte; Bruce D Gelb; Wendy N Nembhard; Martha Werler; Meredith M Howley; Lorenzo Botto; A J Agopian; Omobola O Oluwafemi; Mary M Jenkins; Lynn M Almli; Andy Olshan; Paul A Romitti; Gary Shaw; Ming Li; National Birth Defects Prevention Study

doi:10.1016/j.xhgg.2026.100648

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Identifying Genes Associated with Obstructive Congenital Heart Defects Using a Family-Based Genetic Random Field Method: Results from the National Birth Defects Prevention Study

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Identifying Genes Associated with Obstructive Congenital Heart Defects Using a Family-Based Genetic Random Field Method: Results from the National Birth Defects Prevention Study

Manyan Huang, Nianjun Liu, Stephanie M Ware, John S Witte, Bruce D Gelb, Wendy N Nembhard, Martha Werler, Meredith M Howley, Lorenzo Botto, A J Agopian, …

HGG advances, Vol.7(4), 100648

10/08/2026

DOI: 10.1016/j.xhgg.2026.100648

PMID: 42410936

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Abstract

Congenital heart defects (CHDs) are the most common major congenital anomalies and the leading cause of infant mortality attributable to birth defects. Although substantial progress has been made in the identification of single nucleotide variants (SNVs) associated with CHDs, the genetic etiology of CHDs remains largely unknown. While many studies have focused on common variants, efforts are underway to identify rare variants with heterogeneous effects on CHD development. We applied a family-based genetic random field (FGRF) method to buccal cell DNA specimens collected for the National Birth Defects Prevention Study (NBDPS), including 1,123 case families and 1,481 control families. We and others previously showed that the FGRF method was able to identify rare genetic variants associated with disease outcomes in the presence of disease heterogeneity. In this study, we conducted gene-based association tests for 24,270 genes and identified that SLC44A2 was significantly associated with obstructive CHD risk after Bonferroni adjustment for multiple testing, representing the most robust signal observed in our analyses, while other phase-specific findings require further validation. Our subsequent gene set enrichment analyses supported the likely role of this gene in the biological pathways relevant to CHD development. Our study is complementary to existing genome-wide association studies on CHD risk, providing additional insights into the genetic etiology of these birth defects.

rare variants

family-based association study

congenital heart defects

genetic heterogeneity

Details

Title: Subtitle: Identifying Genes Associated with Obstructive Congenital Heart Defects Using a Family-Based Genetic Random Field Method: Results from the National Birth Defects Prevention Study
Creators: Manyan Huang - Indiana University Bloomington
Nianjun Liu - Indiana University Bloomington
Stephanie M Ware - Indiana University School of Medicine
John S Witte - Stanford University
Bruce D Gelb - Child Health and Development Institute
Wendy N Nembhard - University of Arkansas for Medical Sciences
Martha Werler - Boston University
Meredith M Howley - New York State Department of Health
Lorenzo Botto - University of Utah
A J Agopian - The University of Texas Health Science Center at Houston
Omobola O Oluwafemi - The University of Texas Health Science Center at Houston
Mary M Jenkins - National Center on Birth Defects and Developmental Disabilities
Lynn M Almli - National Center on Birth Defects and Developmental Disabilities
Andy Olshan - University of North Carolina at Chapel Hill
Paul A Romitti - University of Iowa
Gary Shaw - Stanford Medicine
Ming Li - Indiana University Bloomington
National Birth Defects Prevention Study
Resource Type: Journal article
Publication Details: HGG advances, Vol.7(4), 100648
DOI: 10.1016/j.xhgg.2026.100648
PMID: 42410936
NLM abbreviation: HGG Adv
ISSN: 2666-2477
eISSN: 2666-2477
Publisher: Elsevier
Grant note: Centers for Disease Control and Prevention (CDC): 96043, 02081, DD09-001, DD13-003, DD18-001, DD23-001 Birth Defects Study To Evaluate Pregnancy Exposures (BD-STEPS): AR U01DD001306, CA U01DD001302, MA U01D D001300, NC U01DD001308, NY U01DD001304, DD00 1227, TX U01DD001309 National Heart, Lung, and Blood Institute: K01HL140333, R56HL164477, R01HL171194
The authors wish to thank study subjects for their participation in the National Birth Defects Prevention Study (NBDPS) and are appreciative of the contributions made by NBDPS and BD-STEPS scientists and staff. This project was supported through Centers for Disease Control and Prevention (CDC) cooperative agreements under PA #96043, PA #02081, FOA #DD09-001, FOA #DD13-003, NOFO #DD18-001, and NOFO #DD23-001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study (NBDPS) and/or the Birth Defects Study To Evaluate Pregnancy Exposures (BD-STEPS) (AR U01DD001306, CA U01DD001302, MA U01D D001300, NC U01DD001308, NY U01DD001304, and DD00 1227; and TX U01DD001309), and the National Heart, Lung, and Blood Institute under award numbers K01HL140333, R56HL164477, and R01HL171194. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CDC.
Language: English
Electronic publication date: 07/06/2026
Date published: 10/08/2026
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9985182281702771

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