The University of Queensland Diamantina Institute, The University of Queensland, Level 7, 37 Kent St, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Behav Genet. 2021 May;51(3):223-236. doi: 10.1007/s10519-021-10044-0. Epub 2021 Feb 13.
The Classical Twin Method (CTM) compares the similarity of monozygotic (MZ) twins with that of dizygotic (DZ) twins to make inferences about the relative importance of genes and environment in the etiology of individual differences. The design has been applied to thousands of traits across the biomedical, behavioral and social sciences and is arguably the most widely used natural experiment known to science. The fundamental assumption of the CTM is that trait relevant environmental covariation within MZ pairs is the same as that found within DZ pairs, so that zygosity differences in within-pair variance must be due to genetic factors uncontaminated by the environment. This equal environments assumption (EEA) has been, and still is hotly contested, and has been mentioned as a possible contributing factor to the missing heritability conundrum. In this manuscript, we introduce a new model for testing the EEA, which we call the Augmented Classical Twin Design which uses identity by descent (IBD) sharing between DZ twin pairs to estimate separate environmental variance components for MZ and DZ twin pairs, and provides a test of whether these are equal. We show through simulation that given large samples of DZ twin pairs, the model provides unbiased estimates of variance components and valid tests of the EEA under strong assumptions (e.g. no epistatic variance, IBD sharing in DZ twins estimated accurately etc.) which may not hold in reality. Sample sizes in excess of 50,000 DZ twin pairs with genome-wide genetic data are likely to be required in order to detect substantial violations of the EEA with moderate power. Consequently, we recommend that the Augmented Classical Twin Design only be applied to datasets with very large numbers of DZ twin pairs (> 50,000 DZ twin pairs), and given the strong assumptions relating to the absence of epistatic variance, appropriate caution be exercised regarding interpretation of the results.
经典双胞胎方法（CTM）通过比较同卵（MZ）双胞胎和异卵（DZ）双胞胎的相似性，来推断个体差异的基因和环境的相对重要性。该设计已应用于生物医学、行为和社会科学的数千个特征，并且可以说是科学界最广泛使用的自然实验。CTM 的基本假设是，MZ 对子内与性状相关的环境协变量与 DZ 对子内的环境协变量相同，因此对子内方差的同卵性差异一定是由于遗传因素，不受环境影响。这种均等环境假设（EEA）一直存在争议，并且被认为是遗传率缺失之谜的一个可能的促成因素。在本文中，我们引入了一种新的测试 EEA 的模型，我们称之为增强经典双胞胎设计，它使用 DZ 双胞胎之间的血缘关系（IBD）共享来估计 MZ 和 DZ 双胞胎之间的单独环境方差分量，并测试这些分量是否相等。通过模拟我们表明，在具有大量 DZ 双胞胎样本的情况下，该模型提供了方差分量的无偏估计和对 EEA 的有效检验，在强假设下（例如，没有上位方差，DZ 双胞胎中 IBD 共享准确估计等），这些假设在现实中可能不成立。为了以适度的功效检测到对 EEA 的实质性违反，可能需要超过 50,000 对具有全基因组遗传数据的 DZ 双胞胎对的样本量。因此，我们建议仅将增强经典双胞胎设计应用于具有大量 DZ 双胞胎对（>50,000 对 DZ 双胞胎对）的数据集，并且鉴于与不存在上位方差相关的强假设，应谨慎解释结果。
