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. 2014 Sep;133(9):1127-38.
doi: 10.1007/s00439-014-1453-1. Epub 2014 Jun 4.

A genetic association study detects haplotypes associated with obstructive heart defects

Ming Li  1 , Mario A Cleves, Himel Mallick, Stephen W Erickson, Xinyu Tang, Todd G Nick, Stewart L Macleod, Charlotte A Hobbs; National Birth Defect Prevention Study
Affiliations

A genetic association study detects haplotypes associated with obstructive heart defects

Ming Li et al. Hum Genet. 2014 Sep.

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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Figures

Fig. 1
Fig. 1
MGMT (Block 4)—Fetal main effect only. Fetal haplotype H showed an additive effect that was protective of the disease, while the risk of disease was unchanged by maternal genotypes
Fig. 2
Fig. 2
GSTM4 (Block 1)—maternal main effect only. Maternal haplotype H showed an additive effect that was protective of the disease, while the risk of disease was unchanged by fetal genotypes
Fig. 3
Fig. 3
DNMT3L (Block 9)—MFG interaction effect. Maternal and fetal genotypes showed interactive pattern in terms of disease risk
See this image and copyright information in PMC

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