Department of Human Development and Family Studies, The Pennsylvania State University, University Park, PA, USA.
Center for Neuroscience, University of California, Davis, Davis, CA, USA.
Dev Psychopathol. 2023 May;35(2):662-677. doi: 10.1017/S0954579421001796. Epub 2022 Mar 3.
Genetic studies of complex traits often show disparities in estimated heritability depending on the method used, whether by genomic associations or twin and family studies. We present a simulation of individual genomes with dynamic environmental conditions to consider how linear and nonlinear effects, gene-by-environment interactions, and gene-by-environment correlations may work together to govern the long-term development of complex traits and affect estimates of heritability from common methods. Our simulation studies demonstrate that the genetic effects estimated by genome wide association studies in unrelated individuals are inadequate to characterize gene-by-environment interaction, while including related individuals in genome-wide complex trait analysis (GCTA) allows gene-by-environment interactions to be recovered in the heritability. These theoretical findings provide an explanation for the "missing heritability" problem and bridge the conceptual gap between the most common findings of GCTA and twin studies. Future studies may use the simulation model to test hypotheses about phenotypic complexity either in an exploratory way or by replicating well-established observations of specific phenotypes.
复杂性状的遗传研究常常表明，根据所使用的方法（基因组关联或双胞胎和家庭研究），遗传力的估计存在差异。我们提出了一种模拟个体基因组的动态环境条件的方法，以考虑线性和非线性效应、基因-环境相互作用以及基因-环境相关性如何共同作用来控制复杂性状的长期发展，并影响常见方法对遗传力的估计。我们的模拟研究表明，在无关联个体中通过全基因组关联研究估计的遗传效应不足以描述基因-环境相互作用，而在全基因组复杂性状分析（GCTA）中包括相关个体可以在遗传力中恢复基因-环境相互作用。这些理论发现为“遗传力缺失”问题提供了一个解释，并弥合了 GCTA 和双胞胎研究最常见发现之间的概念差距。未来的研究可以使用模拟模型以探索性的方式或通过复制特定表型的既定观察结果来检验关于表型复杂性的假设。
