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,
Hum Genet. 2014 Sep;133(9):1127-38. doi: 10.1007/s00439-014-1453-1. Epub 2014 Jun 4.
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.
先天性心脏病（CHD）的发生涉及遗传变异、表观遗传变异和环境暴露之间的复杂相互作用。先前的研究表明，CHD 的易感性与母体基因型、胎儿基因型和母胎基因型（MFG）相互作用有关。我们进行了基于单体型的阻塞性心脏缺陷（OHD）遗传关联研究，旨在检测涉及同型半胱氨酸、叶酸和转硫途径的 877 个 SNP 的遗传效应。基因型可用于 285 对患有 OHD 的妊娠母婴和 868 对未受影响的妊娠母婴。应用带有自适应最小绝对收缩和选择算子（lasso）的惩罚逻辑回归模型，该模型可分解与 OHD 相关的母体效应、胎儿效应和 MFG 相互作用效应。通过检查 140 个单体型块之间的关联，我们确定了 9 个可能与 OHD 发生相关的单体型块。在贝叶斯错误发现率概率阈值为 0.8 的情况下，MGMT、MTHFS、CBS 和 DNMT3L 基因中的 4 个单体型块具有统计学意义。MGMT 和 MTHFS 中的两个单体型块似乎具有显著的胎儿效应，而 CBS 和 DNMT3L 基因可能具有显著的 MFG 相互作用效应。
