An adaptive test based on principal components for detecting multiple phenotype associations using GWAS summary data

Extensive evidence from genome-wide association studies (GWAS) has shown that jointly analyzing multiple phenotypes can improve the power of the association test compared to the traditional single variant versus single trait approach. Here we propose an adaptive test based on principal components (ATPC) that is powerful and efficient for discovering the association between a single variant and multiple traits. Our method only needs GWAS summary statistics that are often available. We first estimate the trait correlation matrix by LD score regression. Then, based on the correlation matrix, we construct a series of test statistics that contain different numbers of principal components. The ultimate test statistic combines the P values of these principal component-based statistics by using the aggregated Cauchy association test. The analytical P-value of the test statistic can be computed quickly without the permutation process, which is the notable feature of our proposed method. The extensive simulation studies demonstrate that ATPC can control the type I error rates and have powerful and robust performance compared to several existing tests in a wide range of simulation settings. The analysis of the lipids GWAS summary data from the Global Lipids Genetics Consortium shows that ATPC identifies 230 new SNPs that are missed by the original single trait association analysis. By searching the GWAS Catalog, some SNPs and mapped genes identified by ATPC are reported to be associated with lipid traits. Through further analysis for GWAS results, we also find some Gene Ontology terms and biological pathways related to lipids.