Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies

Abstract

Meta-analysis of whole-genome/exome sequencing (WGS/WES) studies provides an attractive solution to obtain large sample sizes from multiple studies for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to large WGS data. Here we propose MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large WGS/WES data. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits, and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans-Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.