COMBAT: A Combined Association Test for Genes Using Summary Statistics

Genome-wide association studies (GWAS) have been widely used for identifying common variants associated with complex diseases. Traditional analysis of GWAS typically examines one marker at a time, usually single nucleotide polymorphisms (SNPs), to identify individual variants associated with a disease. However, due to the small effect sizes of common variants, the power to detect individual risk variants is generally low. As a complementary approach to SNP-level analysis, a variety of gene-based association tests have been proposed. However, the power of existing gene-based tests is often dependent on the underlying genetic models, and it is not known a priori which test is optimal. Here we propose a combined association test (COMBAT) for genes, which incorporates strengths from existing gene-based tests and shows higher overall performance than any individual test. Our method does not require raw genotype or phenotype data, but needs only SNP-level P-values and correlations between SNPs from ancestry-matched samples. Extensive simulations showed that COMBAT has an appropriate type I error rate, maintains higher power across a wide range of genetic models, and is more robust than any individual gene-based test. We further demonstrated the superior performance of COMBAT over several other gene-based tests through reanalysis of the meta-analytic results of GWAS for bipolar disorder. Our method allows for the more powerful application of gene-based analysis to complex diseases, which will have broad use given that GWAS summary results are increasingly publicly available.