Computationally efficient meta-analysis of gene-based tests using summary statistics in large-scale genetic studies

Meta-analysis of gene-based tests using single-variant summary statistics is a powerful strategy for genetic association studies. However, current approaches require sharing the covariance matrix between variants for each study and trait of interest. For large-scale studies with many phenotypes, these matrices can be cumbersome to calculate, store and share. Here, to address this challenge, we present REMETA-an efficient tool for meta-analysis of gene-based tests. REMETA uses a single sparse covariance reference file per study that is rescaled for each phenotype using single-variant summary statistics. We develop new methods for binary traits with case-control imbalance, and to estimate allele frequencies, genotype counts and effect sizes of burden tests. We demonstrate the performance and advantages of our approach through meta-analysis of five traits in 469,376 samples in UK Biobank. The open-source REMETA software will facilitate meta-analysis across large-scale exome sequencing studies from diverse studies that cannot easily be combined.