Young Alexander Strudwick
UCLA Anderson School of Management, Los Angeles, CA, USA.
Human Genetics Department, UCLA David Geffen School of Medicine, Los Angeles, CA, US.
bioRxiv. 2023 Jul 11:2023.07.10.548458. doi: 10.1101/2023.07.10.548458.
Both direct genetic effects (effects of alleles in an individual on that individual) and indirect genetic effects - effects of alleles in an individual (e.g. parents) on another individual (e.g. offspring) - can contribute to phenotypic variation and genotype-phenotype associations. Here, we consider a phenotype affected by direct and parental indirect genetic effects under assortative mating at equilibrium. We generalize classical theory to derive a decomposition of the equilibrium phenotypic variance in terms of direct and indirect genetic effect components. We extend this theory to show that popular methods for estimating indirect genetic effects or 'genetic nurture' through analysis of parental and offspring polygenic predictors (called polygenic indices or scores - PGIs or PGSs) are substantially biased by assortative mating. We propose an improved method for estimating indirect genetic effects while accounting for assortative mating that can also correct heritability estimates for bias due to assortative mating. We validate our method in simulations and apply it to PGIs for height and educational attainment (EA), estimating that the equilibrium heritability of height is 0.699 (S.E. = 0.075 ) and finding no evidence for indirect genetic effects on height. We estimate a very high correlation between parents' underlying genetic components for EA, 0.755 (S.E. = 0.035), which is inconsistent with twin based estimates of the heritability of EA, possibly due to confounding in the EA PGI and/or in twin studies. We implement our method in the software package enabling researchers to apply the method to data including observed and/or imputed parental genotypes. We provide a theoretical framework for understanding the results of PGI analyses and a practical methodology for estimating heritability and indirect genetic effects while accounting for assortative mating.
直接遗传效应（个体中基因对等位基因携带者自身的影响）和间接遗传效应——个体（如父母）中基因对等位基因携带者对另一个体（如后代）的影响——都可能导致表型变异和基因型-表型关联。在此，我们考虑在平衡的选型交配下，受直接和父母间接遗传效应影响的一种表型。我们推广经典理论，以根据直接和间接遗传效应成分来分解平衡表型方差。我们扩展这一理论，以表明通过分析父母和后代的多基因预测因子（称为多基因指数或分数——PGI或PGS）来估计间接遗传效应或“遗传教养”的常用方法，会因选型交配而产生严重偏差。我们提出一种改进方法，在考虑选型交配的同时估计间接遗传效应，该方法还可以校正由于选型交配导致的遗传力估计偏差。我们在模拟中验证了我们的方法，并将其应用于身高和教育程度（EA）的PGI，估计身高的平衡遗传力为0.699（标准误=0.075），且未发现间接遗传效应影响身高的证据。我们估计父母EA潜在遗传成分之间的相关性非常高，为0.755（标准误=0.035），这与基于双胞胎的EA遗传力估计不一致，可能是由于EA的PGI和/或双胞胎研究中存在混杂因素。我们在软件包中实现了我们的方法，使研究人员能够将该方法应用于包括观察到的和/或推断出的父母基因型的数据。我们提供了一个理论框架来理解PGI分析的结果，以及一种实用方法来估计遗传力和间接遗传效应，同时考虑选型交配。
