Adaptively Integrative Association between Multivariate Phenotypes and Transcriptomic Data for Complex Diseases

Phenotype–gene association studies can uncover disease mechanisms for translational research. Association with multiple phenotypes or clinical variables in complex diseases has the advantage of increasing statistical power and offering a holistic view. Existing multi-variate association methods mostly focus on SNP-based genetic associations. In this paper, we extend and evaluate two adaptive Fisher’s methods, namely AFp and AFz, from the p-value combination perspective for phenotype–mRNA association analysis. The proposed method effectively aggregates heterogeneous phenotype–gene effects, allows association with different data types of phenotypes, and performs the selection of the associated phenotypes. Variability indices of the phenotype–gene effect selection are calculated by bootstrap analysis, and the resulting co-membership matrix identifies gene modules clustered by phenotype–gene effect. Extensive simulations demonstrate the superior performance of AFp compared to existing methods in terms of type I error control, statistical power and biological interpretation. Finally, the method is separately applied to three sets of transcriptomic and clinical datasets from lung disease, breast cancer, and brain aging and generates intriguing biological findings.