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A genetic association study detects haplotypes associated with obstructive heart defects

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Abstract

The development of congenital heart defects (CHDs) involves a complex interplay between genetic variants, epigenetic variants, and environmental exposures. Previous studies have suggested that susceptibility to CHDs is associated with maternal genotypes, fetal genotypes, and maternal–fetal genotype (MFG) interactions. We conducted a haplotype-based genetic association study of obstructive heart defects (OHDs), aiming to detect the genetic effects of 877 SNPs involved in the homocysteine, folate, and transsulfuration pathways. Genotypes were available for 285 mother-offspring pairs with OHD-affected pregnancies and 868 mother-offspring pairs with unaffected pregnancies. A penalized logistic regression model was applied with an adaptive least absolute shrinkage and selection operator (lasso), which dissects the maternal effect, fetal effect, and MFG interaction effects associated with OHDs. By examining the association between 140 haplotype blocks, we identified 9 blocks that are potentially associated with OHD occurrence. Four haplotype blocks, located in genes MGMT, MTHFS, CBS, and DNMT3L, were statistically significant using a Bayesian false-discovery probability threshold of 0.8. Two blocks in MGMT and MTHFS appear to have significant fetal effects, while the CBS and DNMT3L genes may have significant MFG interaction effects.

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Acknowledgments

We want to thank two anonymous reviewers for their insightful comments and suggestions. We also wish to thank numerous families for their generous participation in the National Birth Defects Prevention Study that made this research possible. We also thank the Centers for Birth Defects Research and Prevention in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah for their contribution of data and manuscript review. The authors also wish to thank Jingyun Li and Ashley S. Block for assistance in the preparation of this manuscript. This work is supported by the National Institute of Child Health and Human Development (NICHD) under award number 5R01HD039054-12 and the National Center on Birth Defects and Developmental Disabilities (NCBDDD) under award number 5U01DD000491-05. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the Center of Disease Control and Prevention (CDC).

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  1. Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, 13 Children’s Way Mail Slot 512-40, Little Rock, AR, 72202, USA

    Ming Li, Mario A. Cleves, Xinyu Tang, Todd G. Nick, Stewart L. Macleod & Charlotte A. Hobbs

  2. Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA

    Stephen W. Erickson

  3. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

    Himel Mallick

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  1. Ming Li
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Correspondence to Charlotte A. Hobbs.

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Li, M., Cleves, M.A., Mallick, H. et al. A genetic association study detects haplotypes associated with obstructive heart defects. Hum Genet 133, 1127–1138 (2014). https://doi.org/10.1007/s00439-014-1453-1

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