A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Sara R Rashkin; Mario Cleves; Gary M Shaw; Wendy N Nembhard; Eirini Nestoridi; Mary M Jenkins; Paul A Romitti; Xiang-Yang Lou; Marilyn L Browne; Laura E Mitchell; Andrew F Olshan; Kevin Lomangino; Sudeepa Bhattacharyya; John S Witte; Charlotte A Hobbs; National Birth Defects Prevention Study

doi:10.1002/ajmg.a.62759

A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Am J Med Genet A. 2022 Aug;188(8):2303-2314. doi: 10.1002/ajmg.a.62759. Epub 2022 Apr 22.

Authors

Sara R Rashkin¹, Mario Cleves², Gary M Shaw³, Wendy N Nembhard⁴, Eirini Nestoridi⁵, Mary M Jenkins⁶, Paul A Romitti⁷, Xiang-Yang Lou⁸, Marilyn L Browne^{9

10}, Laura E Mitchell¹¹, Andrew F Olshan¹², Kevin Lomangino¹³, Sudeepa Bhattacharyya¹⁴, John S Witte¹, Charlotte A Hobbs¹⁵; National Birth Defects Prevention Study

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
² Department of Pediatrics, Morsani College of Medicine, University of South Florida, Health Informatics Institute, Tampa, Florida, USA.
³ Department of Pediatrics, Stanford University, Stanford, California, USA.
⁴ Department of Epidemiology and Arkansas Center for Birth Defects and Prevention, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
⁵ Massachusetts Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health, Boston, Massachusetts, USA.
⁶ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁷ Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA.
⁸ Department of Biostatistics, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, Florida, USA.
⁹ Birth Defects Research Section, New York State Department of Health, Albany, New York, USA.
¹⁰ Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA.
¹¹ Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, Texas, USA.
¹² Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
¹³ Kaufman Wills Fusting & Company, Baltimore, Maryland, USA.
¹⁴ Bioinformatics and Data Science at University of Arkansas, Little Rock, Arkansas, USA.
¹⁵ Rady Children's Institute for Genomic Medicine, San Diego, California, USA.

Abstract

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (N_discovery = 3978; N_replication = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (N_{discovery_TDT} = 440; N_{replication_TDT} = 275) and case-control analyses separately in infants (N_{discovery_CCI} = 1635; N_{replication_CCI} = 990) and mothers (case status defined by infant; N_{discovery_CCM} = 1703; N_{replication_CCM} = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (p_discovery = 4.08 × 10^-9 ; p_replication = 2.44 × 10^-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (p_discovery = 1.61 × 10^-7 ; p_replication = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10^-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds ( × _discovery < 1 × 10^-5 and p_replication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (p_discovery = 1.42 × 10^-6 ; p_replication = 0.04). Additional SNPs with p_discovery < 1 × 10^-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.

Keywords: CAPN11; GWAS; National Birth Defects Prevention Study; SLC44A2; congenital heart defects; obstructive heart defects.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Case-Control Studies
Female
Genetic Predisposition to Disease
Genome-Wide Association Study*
Heart Defects, Congenital* / epidemiology
Heart Defects, Congenital* / genetics
Humans
Infant
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding