Joint analysis of multiple phenotypes using a clustering linear combination method based on hierarchical clustering.

Emerging evidence suggests that a genetic variant can affect multiple phenotypes, especially in complex human diseases. Therefore, joint analysis of multiple phenotypes may offer new insights into disease etiology. Recently, many statistical methods have been developed for joint analysis of multiple phenotypes, including the clustering linear combination (CLC) method. Due to the unknown number of clusters for a given data, a simulation procedure must be used to evaluate the p-value of the final test statistic of CLC. This makes the CLC method computationally demanding. In this paper, we use a stopping criterion to determine the number of clusters in the CLC method. We have named our method, hierarchical clustering CLC (HCLC). HCLC has an asymptotic distribution, which is very computationally efficient and makes it applicable for genome-wide association studies. Extensive simulations together with the COPDGene data analysis have been used to assess the type I error rates and power of our proposed method. Our simulation results demonstrate that the type I error rates of HCLC are effectively controlled in different realistic settings. HCLC either outperforms all other methods or has statistical power that is very close to the most powerful method with which it has been compared.