Genes, including those with transgenerational effects, work in concert with behavioral, environmental, and social factors via complex biological networks to determine human health. Understanding complex relationships between causal factors underlying human health is an essential step towards deciphering biological mechanisms. We propose a new analytical framework to investigate the interactions between maternal and offspring genetic variants or their surrogate single nucleotide polymorphisms (SNPs) and environmental factors using family‐based hybrid study design. The proposed approach can analyze diverse genetic and environmental factors and accommodate samples from a variety of family units, including case/control–parental triads, and case/control–parental dyads, while minimizing potential bias introduced by population admixture. Comprehensive simulations demonstrated that our innovative approach outperformed the log‐linear approach, the best available method for case–control family data. The proposed approach had greater statistical power and was capable to unbiasedly estimate the maternal and child genetic effects and the effects of environmental factors, while controlling the Type I error rate against population stratification. Using our newly developed approach, we analyzed the associations between maternal and fetal SNPs and obstructive and conotruncal heart defects, with adjustment for demographic and lifestyle factors and dietary supplements. Fourteen and 11 fetal SNPs were associated with obstructive and conotruncal heart defects, respectively. Twenty‐seven and 17 maternal SNPs were associated with obstructive and conotruncal heart defects, respectively. In addition, maternal body mass index was a significant risk factor for obstructive defects. The proposed approach is a powerful tool for interrogating the etiological mechanism underlying complex traits.

中文翻译：

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在基于家庭的混合设计中识别与出生缺陷相关的多基因组和环境相互作用的创新方法


基因，包括具有跨代效应的基因，通过复杂的生物网络与行为、环境和社会因素协同作用，从而决定人类健康。了解人类健康的因果因素之间的复杂关系是破译生物学机制的重要一步。我们提出了一个新的分析框架，使用基于家庭的混合研究设计来研究母体和后代遗传变异或其替代单核苷酸多态性（SNP）与环境因素之间的相互作用。所提出的方法可以分析不同的遗传和环境因素，并适应来自各种家庭单位的样本，包括病例/对照-父母三联体和病例/对照-父母二元组，同时最大限度地减少人口混合引入的潜在偏差。综合模拟表明，我们的创新方法优于对数线性方法，这是病例对照家庭数据的最佳可用方法。所提出的方法具有更大的统计功效，能够公正地估计母婴遗传效应和环境因素的影响，同时控制人口分层的I类错误率。使用我们新开发的方法，我们分析了母体和胎儿 SNP 与阻塞性和圆锥干心脏缺陷之间的关联，并根据人口和生活方式因素以及膳食补充剂进行了调整。 14 个和 11 个胎儿 SNP 分别与阻塞性和圆锥干心脏缺陷相关。 27 个和 17 个母体 SNP 分别与阻塞性和圆锥干心脏缺陷相关。此外，母亲体重指数是阻塞性缺陷的重要危险因素。 所提出的方法是询问复杂性状背后的病因机制的有力工具。