Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90032, USA.
Genet Epidemiol. 2013 Jul;37(5):440-51. doi: 10.1002/gepi.21720. Epub 2013 Apr 30.
Exhaustive testing of all possible SNP pairs in a genome-wide association study (GWAS) generally yields low power to detect gene-gene (G × G) interactions because of small effect sizes and stringent requirements for multiple-testing correction. We introduce a new two-step procedure for testing G × G interactions in case-control GWAS to detect interacting single nucleotide polymorphisms (SNPs) regardless of their marginal effects. In an initial screening step, all SNP pairs are tested for gene-gene association in the combined sample of cases and controls. In the second step, the pairs that pass the screening are followed up with a traditional test for G × G interaction. We show that the two-step method is substantially more powerful to detect G × G interactions than the exhaustive testing approach. For example, with 2,000 cases and 2,000 controls, the two-step method can have more than 90% power to detect an interaction odds ratio of 2.0 compared to less than 50% power for the exhaustive testing approach. Moreover, we show that a hybrid two-step approach that combines our newly proposed two-step test and the two-step test that screens for marginal effects retains the best power properties of both. The two-step procedures we introduce have the potential to uncover genetic signals that have not been previously identified in an initial single-SNP GWAS. We demonstrate the computational feasibility of the two-step G × G procedure by performing a G × G scan in the asthma GWAS of the University of Southern California Children's Health Study.
在全基因组关联研究（GWAS）中对所有可能的 SNP 对进行详尽测试通常由于效应量小和多重检验校正的严格要求，导致检测基因-基因（G×G）相互作用的能力较低。我们介绍了一种新的两步程序，用于在病例对照 GWAS 中测试 G×G 相互作用，以检测相互作用的单核苷酸多态性（SNP），而不考虑其边缘效应。在初始筛选步骤中，在病例和对照的组合样本中测试所有 SNP 对的基因-基因关联。在第二步中，通过传统的 G×G 相互作用检验来跟进通过筛选的对。我们表明，两步法在检测 G×G 相互作用方面的功效大大高于详尽测试方法。例如，对于 2000 例病例和 2000 例对照，两步法检测交互作用比值为 2.0 的功效超过 90%，而详尽测试方法的功效则低于 50%。此外，我们表明，结合我们新提出的两步检验和筛选边缘效应的两步检验的混合两步方法保留了两者的最佳功效特性。我们介绍的两步程序有可能揭示以前在初始单 SNP GWAS 中未发现的遗传信号。我们通过在南加州大学儿童健康研究的哮喘 GWAS 中进行 G×G 扫描，证明了两步 G×G 程序的计算可行性。
