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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.
摘要：
先天性心脏病（CHD）的发展涉及遗传变异之间复杂的相互作用，表观遗传变异，和环境暴露。以前的研究表明，对CHD的易感性与母体基因型有关，胎儿基因型,和母胎基因型（MFG）相互作用。我们进行了基于单倍型的阻塞性心脏缺陷（OHD）的遗传关联研究，旨在检测877个SNPs参与同型半胱氨酸的遗传效应,叶酸,和转硫途径。基因型可用于285对OHD受影响怀孕的母子对和868对未受影响怀孕的母子对。采用自适应最小绝对收缩和选择算子(套索)的惩罚逻辑回归模型，剖析了母体的影响，胎儿效应,以及与OHD相关的MFG相互作用效应。通过检查140个单倍型区块之间的关联，我们确定了9个可能与OHD发生相关的区块.四个单倍型区块，位于MGMT基因中，MTHFS,CBS,和DNMT3L，使用0.8的贝叶斯错误发现概率阈值具有统计学意义。MGMT和MTHFS中的两个区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互作效应。
