Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

TitleDynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.
Publication TypeJournal Article
Year of Publication2020
AuthorsLi, X, Li, Z, Zhou, H, Gaynor, SM, Liu, Y, Chen, H, Sun, R, Dey, R, Arnett, DK, Aslibekyan, S, Ballantyne, CM, Bielak, LF, Blangero, J, Boerwinkle, E, Bowden, DW, Broome, JG, Conomos, MP, Correa, A, L Cupples, A, Curran, JE, Freedman, BI, Guo, X, Hindy, G, Irvin, MR, Kardia, SLR, Kathiresan, S, Khan, AT, Kooperberg, CL, Laurie, CC, X Liu, S, Mahaney, MC, Manichaikul, AW, Martin, LW, Mathias, RA, McGarvey, ST, Mitchell, BD, Montasser, ME, Moore, JE, Morrison, AC, O'Connell, JR, Palmer, ND, Pampana, A, Peralta, JM, Peyser, PA, Psaty, BM, Redline, S, Rice, KM, Rich, SS, Smith, JA, Tiwari, HK, Tsai, MY, Vasan, RS, Wang, FFei, Weeks, DE, Weng, Z, Wilson, JG, Yanek, LR, Neale, BM, Sunyaev, SR, Abecasis, GR, Rotter, JI, Willer, CJ, Peloso, GM, Natarajan, P, Lin, X
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group
JournalNat Genet
Volume52
Issue9
Pagination969-983
Date Published2020 09
ISSN1546-1718
KeywordsCholesterol, LDL, Computer Simulation, Genetic Predisposition to Disease, Genetic Variation, Genome, Genome-Wide Association Study, Humans, Models, Genetic, Molecular Sequence Annotation, Phenotype, Whole Genome Sequencing
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.

DOI10.1038/s41588-020-0676-4
Alternate JournalNat Genet
PubMed ID32839606
PubMed Central IDPMC7483769
Grant ListN01HC95162 / HL / NHLBI NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
R01 MH078111 / MH / NIMH NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
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M01 RR000052 / RR / NCRR NIH HHS / United States
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R35 HL135818 / HL / NHLBI NIH HHS / United States
T32 GM074897 / GM / NIGMS NIH HHS / United States
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P01 CA134294 / CA / NCI NIH HHS / United States
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HHSN268201700003I / HL / NHLBI NIH HHS / United States
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