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Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies
Journal article   Open access   Peer reviewed

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

Xihao Li, Corbin Quick, Hufeng Zhou, Sheila M Gaynor, Yaowu Liu, Han Chen, Margaret Sunitha Selvaraj, Ryan Sun, Rounak Dey, Donna K Arnett, …
Nature genetics, Vol.55(1), pp.154-164
01/2023
DOI: 10.1038/s41588-022-01225-6
PMCID: PMC10084891
PMID: 36564505

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Abstract

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. 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.
 Phenotype Exome Sequencing Genome-Wide Association Study - methods Lipids - genetics Whole Genome Sequencing - methods

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