Association Tests of Multiple Phenotypes: ATeMP

Joint analysis of multiple phenotypes has gained growing attention in genome-wide association studies (GWASs), especially for the analysis of multiple intermediate phenotypes which measure the same underlying complex human disorder. One of the multivariate methods, MultiPhen (O’ Reilly et al. 2012), employs the proportional odds model to regress a genotype on multiple phenotypes, hence ignoring the phenotypic distributions. Despite the flexibilities of MultiPhen, the properties and performance of MultiPhen are not well understood, especially when the phenotypic distributions are non-normal. In fact, it is well known in the statistical literature that the estimation is attenuated when the explanatory variables contain measurement errors. In this study, we first established an equivalence relationship between MultiPhen and the generalized Kendall tau association test, shedding light on why MultiPhen can perform well for joint association analysis of multiple phenotypes. Through the equivalence, we show that MultiPhen may lose power when the phenotypes are non-normal. To maintain the power, we propose two solutions (ATeMP-rn and ATeMP-or) to improve MultiPhen, and demonstrate their effectiveness through extensive simulation studies and a real case study from the Guangzhou Twin Eye Study.