Verhulst Brad, Eaves Lindon J, Neale Michael C
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine (VCU), Box 980126, Richmond, VA, 23298-0126, USA,
Behav Genet. 2014 Jul;44(4):337-46. doi: 10.1007/s10519-014-9650-1. Epub 2014 Mar 20.
Twin and family studies implicitly assume that the covariation between family members remains constant across differences in age between the members of the family. However, age-specificity in gene expression for shared environmental factors could generate higher correlations between family members who are more similar in age. Cohort effects (cohort × genotype or cohort × common environment) could have the same effects, and both potentially reduce effect sizes estimated in genome-wide association studies where the subjects are heterogeneous in age. In this paper we describe a model in which the covariance between twins and non-twin siblings is moderated as a function of age difference. We describe the details of the model and simulate data using a variety of different parameter values to demonstrate that model fitting returns unbiased parameter estimates. Power analyses are then conducted to estimate the sample sizes required to detect the effects of moderation in a design of twins and siblings. Finally, the model is applied to data on cigarette smoking. We find that (1) the model effectively recovers the simulated parameters, (2) the power is relatively low and therefore requires large sample sizes before small to moderate effect sizes can be found reliably, and (3) the genetic covariance between siblings for smoking behavior decays very rapidly. Result 3 implies that, e.g., genome-wide studies of smoking behavior that use individuals assessed at different ages, or belonging to different birth-year cohorts may have had substantially reduced power to detect effects of genotype on cigarette use. It also implies that significant special twin environmental effects can be explained by age-moderation in some cases. This effect likely contributes to the missing heritability paradox.
双胞胎和家族研究隐含地假设，家庭成员之间的协变在家族成员年龄差异范围内保持恒定。然而，共享环境因素的基因表达中的年龄特异性可能会在年龄更相近的家庭成员之间产生更高的相关性。队列效应（队列×基因型或队列×共同环境）可能会产生相同的影响，并且这两者都可能降低在全基因组关联研究中估计的效应量，在这些研究中，受试者的年龄是异质的。在本文中，我们描述了一个模型，其中双胞胎和非双胞胎兄弟姐妹之间的协变作为年龄差异的函数进行调节。我们描述了该模型的细节，并使用各种不同的参数值模拟数据，以证明模型拟合返回无偏参数估计。然后进行功效分析，以估计在双胞胎和兄弟姐妹设计中检测调节效应所需的样本量。最后，将该模型应用于吸烟数据。我们发现：（1）该模型有效地恢复了模拟参数；（2）功效相对较低，因此在可靠地发现小到中等效应量之前需要大样本量；（3）兄弟姐妹之间吸烟行为的遗传协变衰减非常迅速。结果3意味着，例如，对吸烟行为进行的全基因组研究，如果使用不同年龄评估的个体或属于不同出生队列的个体，可能会大大降低检测基因型对吸烟影响的功效。这也意味着在某些情况下，显著的特殊双胞胎环境效应可以通过年龄调节来解释。这种效应可能导致了遗传力缺失悖论。
