Journal article
Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale
Nature genetics, Vol.52(9), pp.969-983
09/2020
DOI: 10.1038/s41588-020-0676-4
PMCID: PMC7483769
PMID: 32839606
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 '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.
Details
- Title: Subtitle
- Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale
- Creators
- Xihao Li - Harvard UniversityBarry I Freedman - Wake Forest UniversityXiuqing Guo - The Lundquist InstituteZilin Li - Harvard UniversityGeorge Hindy - Qatar UniversityHufeng Zhou - Harvard UniversitySheila M Gaynor - Harvard UniversityMarguerite R Irvin - University of Alabama at BirminghamYaowu Liu - Southwestern University of Finance and EconomicsSharon L R Kardia - University of MichiganSekar Kathiresan - Harvard UniversityHan Chen - The University of Texas Health Science Center at HoustonAlyna T Khan - University of WashingtonRyan Sun - The University of Texas MD Anderson Cancer CenterRounak Dey - Harvard UniversityCharles L Kooperberg - Fred Hutch Cancer CenterCathy C Laurie - University of WashingtonDonna K Arnett - University of KentuckyStella Aslibekyan - University of Alabama at BirminghamX Shirley Liu - Harvard UniversityChristie M Ballantyne - Baylor College of MedicineMichael C Mahaney - The University of Texas Rio Grande ValleyLawrence F Bielak - University of MichiganAni W Manichaikul - University of VirginiaJohn Blangero - The University of Texas Rio Grande ValleyLisa W Martin - George Washington UniversityRasika A Mathias - Johns Hopkins MedicineEric Boerwinkle - Baylor College of MedicineStephen T McGarvey - Brown UniversityDonald W Bowden - Wake Forest UniversityJai G Broome - University of WashingtonBraxton D Mitchell - University of Maryland, BaltimoreMatthew P Conomos - University of WashingtonMay E Montasser - University of Maryland, BaltimoreJill E Moore - University of Massachusetts Chan Medical SchoolAdolfo Correa - University of Mississippi Medical CenterL Adrienne Cupples - Boston UniversityAlanna C Morrison - The University of Texas Health Science Center at HoustonJeffrey R O'Connell - University of Maryland, BaltimoreJoanne E Curran - The University of Texas Rio Grande ValleyNicholette D Palmer - Wake Forest UniversityAkhil Pampana - Broad InstituteJuan M Peralta - The University of Texas Rio Grande ValleyPatricia A Peyser - University of MichiganBruce M Psaty - University of WashingtonSusan Redline - Harvard UniversityKenneth M Rice - University of WashingtonStephen S Rich - University of VirginiaJennifer A Smith - University of MichiganHemant K Tiwari - University of Alabama at BirminghamMichael Y Tsai - University of MinnesotaRamachandran S Vasan - Boston UniversityFei Fei Wang - University of WashingtonDaniel E Weeks - University of PittsburghZhiping Weng - University of Massachusetts Chan Medical SchoolJames G Wilson - University of Mississippi Medical CenterLisa R Yanek - Johns Hopkins MedicineBenjamin M Neale - Broad InstituteShamil R Sunyaev - Broad InstituteGonçalo R Abecasis - University of MichiganJerome I Rotter - The Lundquist InstituteCristen J Willer - University of MichiganGina M Peloso - Boston UniversityPradeep Natarajan - Broad InstituteXihong Lin - Broad InstituteNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Contributors
- Karin Hoth (Contributor) - University of Iowa, Psychiatry
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.52(9), pp.969-983
- DOI
- 10.1038/s41588-020-0676-4
- PMID
- 32839606
- PMCID
- PMC7483769
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Grant note
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- Language
- English
- Date published
- 09/2020
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984293654902771
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