@article{a0f03fd6906247629d0badc058032ef2,
title = "Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies",
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.",
author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group} and Xihao Li and Corbin Quick and Hufeng Zhou and Gaynor, {Sheila M.} and Yaowu Liu and Han Chen and Selvaraj, {Margaret Sunitha} and Ryan Sun and Rounak Dey and Arnett, {Donna K.} and Bielak, {Lawrence F.} and Bis, {Joshua C.} and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Brody, {Jennifer A.} and Cade, {Brian E.} and Adolfo Correa and Cupples, {L. Adrienne} and Curran, {Joanne E.} and {de Vries}, {Paul S.} and Ravindranath Duggirala and Freedman, {Barry I.} and G{\"o}ring, {Harald H.H.} and Xiuqing Guo and Jeffrey Haessler and Kalyani, {Rita R.} and Charles Kooperberg and Kral, {Brian G.} and Lange, {Leslie A.} and Ani Manichaikul and Martin, {Lisa W.} and McGarvey, {Stephen T.} and Mitchell, {Braxton D.} and Montasser, {May E.} and Morrison, {Alanna C.} and Take Naseri and O{\textquoteright}Connell, {Jeffrey R.} and Palmer, {Nicholette D.} and Peyser, {Patricia A.} and Psaty, {Bruce M.} and Raffield, {Laura M.} and Susan Redline and Reiner, {Alexander P.} and Reupena, {Muagututi{\textquoteright}a Sefuiva} and Rice, {Kenneth M.} and Rich, {Stephen S.} and Sitlani, {Colleen M.} and Smith, {Jennifer A.} and {de Andrade}, Mariza",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
doi = "10.1038/s41588-022-01225-6",
language = "English (US)",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
}