@article{80b0a32307914004b820da1440a8da61,
title = "Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale",
abstract = "Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce {\textquoteleft}annotation principal components{\textquoteright}, multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.",
author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and {TOPMed Lipids Working Group} and Xihao Li and Zilin Li and Hufeng Zhou and Gaynor, {Sheila M.} and Yaowu Liu and Han Chen and Ryan Sun and Rounak Dey and Arnett, {Donna K.} and Stella Aslibekyan and Ballantyne, {Christie M.} and Bielak, {Lawrence F.} and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Broome, {Jai G.} and Conomos, {Matthew P.} and Adolfo Correa and Cupples, {L. Adrienne} and Curran, {Joanne E.} and Freedman, {Barry I.} and Xiuqing Guo and George Hindy and Irvin, {Marguerite R.} and Kardia, {Sharon L.R.} and Sekar Kathiresan and Khan, {Alyna T.} and Kooperberg, {Charles L.} and Laurie, {Cathy C.} and Liu, {X. Shirley} and Mahaney, {Michael C.} and Manichaikul, {Ani W.} and Martin, {Lisa W.} and Mathias, {Rasika A.} and McGarvey, {Stephen T.} and Mitchell, {Braxton D.} and Montasser, {May E.} and Moore, {Jill E.} and Morrison, {Alanna C.} and O{\textquoteright}Connell, {Jeffrey R.} and Palmer, {Nicholette D.} and Akhil Pampana and Peralta, {Juan M.} and Peyser, {Patricia A.} and Psaty, {Bruce M.} and Susan Redline and Rice, {Kenneth M.} and Rich, {Stephen S.} and Smith, {Jennifer A.} and Meyers, {Deborah A.}",
note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = sep,
day = "1",
doi = "10.1038/s41588-020-0676-4",
language = "English (US)",
volume = "52",
pages = "969--983",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "9",
}