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AuthorLi, Xihao
AuthorLi, Zilin
AuthorZhou, Hufeng
AuthorGaynor, Sheila M.
AuthorLiu, Yaowu
AuthorChen, Han
AuthorSun, Ryan
AuthorDey, Rounak
AuthorArnett, Donna K.
AuthorAslibekyan, Stella
AuthorBallantyne, Christie M.
AuthorBielak, Lawrence F.
AuthorBlangero, John
AuthorBoerwinkle, Eric
AuthorBowden, Donald W.
AuthorBroome, Jai G.
AuthorConomos, Matthew P.
AuthorCorrea, Adolfo
AuthorCupples, L. Adrienne
AuthorCurran, Joanne E.
AuthorFreedman, Barry I.
AuthorGuo, Xiuqing
AuthorHindy, George
AuthorIrvin, Marguerite R.
AuthorKardia, Sharon L.R.
AuthorKathiresan, Sekar
AuthorKhan, Alyna T.
AuthorKooperberg, Charles L.
AuthorLaurie, Cathy C.
AuthorLiu, X. Shirley
AuthorMahaney, Michael C.
AuthorManichaikul, Ani W.
AuthorMartin, Lisa W.
AuthorMathias, Rasika A.
AuthorMcGarvey, Stephen T.
AuthorMitchell, Braxton D.
AuthorMontasser, May E.
AuthorMoore, Jill E.
AuthorMorrison, Alanna C.
AuthorO’Connell, Jeffrey R.
AuthorPalmer, Nicholette D.
AuthorPampana, Akhil
AuthorPeralta, Juan M.
AuthorPeyser, Patricia A.
AuthorPsaty, Bruce M.
AuthorRedline, Susan
AuthorRice, Kenneth M.
AuthorRich, Stephen S.
AuthorSmith, Jennifer A.
AuthorTiwari, Hemant K.
AuthorTsai, Michael Y.
AuthorVasan, Ramachandran S.
AuthorWang, Fei Fei
AuthorWeeks, Daniel E.
AuthorWeng, Zhiping
AuthorWilson, James G.
AuthorYanek, Lisa R.
AuthorAbe, Namiko
AuthorAbecasis, Gonçalo R.
AuthorAguet, Francois
AuthorAlbert, Christine
AuthorAlmasy, Laura
AuthorAlonso, Alvaro
AuthorAment, Seth
AuthorAnderson, Peter
AuthorAnugu, Pramod
AuthorApplebaum-Bowden, Deborah
AuthorArdlie, Kristin
AuthorArking, Dan
AuthorAshley-Koch, Allison
AuthorAssimes, Tim
AuthorAuer, Paul
AuthorAvramopoulos, Dimitrios
AuthorBarnard, John
AuthorBarnes, Kathleen
AuthorBarr, R. Graham
AuthorBarron-Casella, Emily
AuthorBarwick, Lucas
AuthorBeaty, Terri
AuthorBeck, Gerald
AuthorBecker, Diane
AuthorBecker, Lewis
AuthorBeer, Rebecca
AuthorBeitelshees, Amber
AuthorBenjamin, Emelia
AuthorBenos, Takis
AuthorBezerra, Marcos
AuthorBis, Joshua
AuthorBlackwell, Thomas
AuthorBowler, Russell
AuthorBrody, Jennifer
AuthorBroeckel, Ulrich
AuthorBunting, Karen
Available date2021-01-31T08:57:04Z
Publication Date2020-09-01
Publication NameNature Genetics
Identifierhttp://dx.doi.org/10.1038/s41588-020-0676-4
CitationLi, X., Li, Z., Zhou, H. et al. Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale. Nat Genet 52, 969–983 (2020). https://doi.org/10.1038/s41588-020-0676-4
ISSN10614036
URIhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85089736482&origin=inward
URIhttp://hdl.handle.net/10576/17547
AbstractLarge-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 ‘annotation principal components’, 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.
Languageen
PublisherNature Research
SubjectGenetic Association
Rare Variant Association Analysis
TitleDynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale
TypeArticle
Pagination969-983
Issue Number9
Volume Number52
dc.accessType Abstract Only


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