Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
JAMA Psychiatry. 2014 Dec 1;71(12):1392-9. doi: 10.1001/jamapsychiatry.2014.1339.
Genetic association studies of psychiatric outcomes often consider interactions with environmental exposures and, in particular, apply tests that jointly consider gene and gene-environment interaction effects for analysis. Using a genome-wide association study (GWAS) of posttraumatic stress disorder (PTSD), we report that heteroscedasticity (defined as variability in outcome that differs by the value of the environmental exposure) can invalidate traditional joint tests of gene and gene-environment interaction.
To identify the cause of bias in traditional joint tests of gene and gene-environment interaction in a PTSD GWAS and determine whether proposed robust joint tests are insensitive to this problem.
DESIGN, SETTING, AND PARTICIPANTS: The PTSD GWAS data set consisted of 3359 individuals (978 men and 2381 women) from the Grady Trauma Project (GTP), a cohort study from Atlanta, Georgia. The GTP performed genome-wide genotyping of participants and collected environmental exposures using the Childhood Trauma Questionnaire and Trauma Experiences Inventory.
We performed joint interaction testing of the Beck Depression Inventory and modified PTSD Symptom Scale in the GTP GWAS. We assessed systematic bias in our interaction analyses using quantile-quantile plots and genome-wide inflation factors.
Application of the traditional joint interaction test to the GTP GWAS yielded systematic inflation across different outcomes and environmental exposures (inflation-factor estimates ranging from 1.07 to 1.21), whereas application of the robust joint test to the same data set yielded no such inflation (inflation-factor estimates ranging from 1.01 to 1.02). Simulated data further revealed that the robust joint test is valid in different heteroscedasticity models, whereas the traditional joint test is invalid. The robust joint test also has power similar to the traditional joint test when heteroscedasticity is not an issue.
We believe the robust joint test should be used in candidate-gene studies and GWASs of psychiatric outcomes that consider environmental interactions. To make the procedure useful for applied investigators, we created a software tool that can be called from the popular PLINK package for analysis.
精神疾病结果的遗传关联研究通常考虑与环境暴露的相互作用，特别是应用联合检验同时考虑基因和基因-环境相互作用的效应进行分析。我们利用创伤后应激障碍（PTSD）的全基因组关联研究（GWAS）报告称，异方差性（定义为因环境暴露值而异的结果变异性）会使传统的基因和基因-环境相互作用联合检验无效。
确定在 PTSD GWAS 中传统基因和基因-环境相互作用联合检验中偏倚的原因，并确定所提出的稳健联合检验是否对该问题不敏感。
设计、设置和参与者：PTSD GWAS 数据集由来自佐治亚州亚特兰大的 Grady Trauma Project（GTP）队列研究的 3359 名个体（978 名男性和 2381 名女性）组成。GTP 对参与者进行了全基因组基因分型，并使用童年创伤问卷和创伤经历量表收集环境暴露数据。
我们在 GTP GWAS 中对 Beck 抑郁量表和改良 PTSD 症状量表进行了联合交互检验。我们使用分位数-分位数图和全基因组膨胀因子评估我们的交互分析中的系统偏差。
传统联合交互检验应用于 GTP GWAS 会导致不同结局和环境暴露的系统性膨胀（膨胀因子估计值在 1.07 到 1.21 之间），而相同数据集中应用稳健联合检验则不会出现这种膨胀（膨胀因子估计值在 1.01 到 1.02 之间）。模拟数据进一步表明，稳健联合检验在不同异方差模型中是有效的，而传统联合检验则是无效的。当异方差不是问题时，稳健联合检验的功效也与传统联合检验相似。
我们认为，在考虑环境相互作用的候选基因研究和精神疾病结果的 GWAS 中，应该使用稳健的联合检验。为了使该程序对应用研究人员有用，我们创建了一个可从流行的 PLINK 包调用的软件工具进行分析。
