Title | A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Li, Z, Li, X, Zhou, H, Gaynor, SM, Selvaraj, MSunitha, Arapoglou, T, Quick, C, Liu, Y, Chen, H, Sun, R, Dey, R, Arnett, DK, Auer, PL, Bielak, LF, Bis, JC, Blackwell, TW, Blangero, J, Boerwinkle, E, Bowden, DW, Brody, JA, Cade, BE, Conomos, MP, Correa, A, L Cupples, A, Curran, JE, de Vries, PS, Duggirala, R, Franceschini, N, Freedman, BI, Göring, HHH, Guo, X, Kalyani, RR, Kooperberg, C, Kral, BG, Lange, LA, Lin, BM, Manichaikul, A, Manning, AK, Martin, LW, Mathias, RA, Meigs, JB, Mitchell, BD, Montasser, ME, Morrison, AC, Naseri, T, O'Connell, JR, Palmer, ND, Peyser, PA, Psaty, BM, Raffield, LM, Redline, S, Reiner, AP, Reupena, M'aSefuiva, Rice, KM, Rich, SS, Smith, JA, Taylor, KD, Taub, MA, Vasan, RS, Weeks, DE, Wilson, JG, Yanek, LR, Zhao, W, Rotter, JI, Willer, CJ, Natarajan, P, Peloso, GM, Lin, X |
Corporate Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group |
Journal | Nat Methods |
Volume | 19 |
Issue | 12 |
Pagination | 1599-1611 |
Date Published | 2022 Dec |
ISSN | 1548-7105 |
Keywords | Genetic Variation, Genome, Genome-Wide Association Study, Humans, Phenotype, Whole Genome Sequencing |
Abstract | Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits. |
DOI | 10.1038/s41592-022-01640-x |
Alternate Journal | Nat Methods |
PubMed ID | 36303018 |
PubMed Central ID | PMC10008172 |
Grant List | 75N92020D00005 / HL / NHLBI NIH HHS / United States R01 DK078616 / DK / NIDDK NIH HHS / United States U01 HG007417 / HG / NHGRI NIH HHS / United States R01 HL112064 / HL / NHLBI NIH HHS / United States KL2 TR001100 / TR / NCATS NIH HHS / United States UM1 AI069423 / AI / NIAID NIH HHS / United States F30 HL149180 / HL / NHLBI NIH HHS / United States R01 HL113323 / HL / NHLBI NIH HHS / United States R01 HL132947 / HL / NHLBI NIH HHS / United States P30 DK040561 / DK / NIDDK NIH HHS / United States U01 HL137183 / HL / NHLBI NIH HHS / United States P30 CA016672 / CA / NCI NIH HHS / United States R01 HL104135 / HL / NHLBI NIH HHS / United States T32 HL144442 / HL / NHLBI NIH HHS / United States R35 CA197449 / CA / NCI NIH HHS / United States P30 ES010126 / ES / NIEHS NIH HHS / United States R01 HL123915 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01 HL046380 / HL / NHLBI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States 75N92020D00003 / HL / NHLBI NIH HHS / United States K01 AG059898 / AG / NIA NIH HHS / United States R01 HL155742 / HL / NHLBI NIH HHS / United States U01 DK085524 / DK / NIDDK NIH HHS / United States KL2 TR002542 / TR / NCATS NIH HHS / United States R03 HL141439 / HL / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States U01 DK062413 / DK / NIDDK NIH HHS / United States R01 HL109946 / HL / NHLBI NIH HHS / United States K01 HL136700 / HL / NHLBI NIH HHS / United States R01 HG006703 / HG / NHGRI NIH HHS / United States U19 CA203654 / CA / NCI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States U01 HG012064 / HG / NHGRI NIH HHS / United States P30 ES005605 / ES / NIEHS NIH HHS / United States R01 AR042742 / AR / NIAMS NIH HHS / United States R21 HL140385 / HL / NHLBI NIH HHS / United States HHSN268201800015I / HB / NHLBI NIH HHS / United States R01 DK113003 / DK / NIDDK NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States R01 HL117191 / HL / NHLBI NIH HHS / United States R01 HG009974 / HG / NHGRI NIH HHS / United States R24 AG047115 / AG / NIA NIH HHS / United States P01 HL107202 / HL / NHLBI NIH HHS / United States P50 HL118006 / HL / NHLBI NIH HHS / United States U01 HL120393 / HL / NHLBI NIH HHS / United States R01 DK117445 / DK / NIDDK NIH HHS / United States R01 HL153805 / HL / NHLBI NIH HHS / United States R01 AG058921 / AG / NIA NIH HHS / United States R01 HL129132 / HL / NHLBI NIH HHS / United States R01 HL113338 / HL / NHLBI NIH HHS / United States HHSN268201800012I / HB / NHLBI NIH HHS / United States R01 HL137922 / HL / NHLBI NIH HHS / United States R01 AI079139 / AI / NIAID NIH HHS / United States R01 DK110113 / DK / NIDDK NIH HHS / United States U19 AI111224 / AI / NIAID NIH HHS / United States R35 HL135824 / HL / NHLBI NIH HHS / United States 75N92019D00031 / HL / NHLBI NIH HHS / United States R01 HL138737 / HL / NHLBI NIH HHS / United States P30 DK079626 / DK / NIDDK NIH HHS / United States R01 NS058700 / NS / NINDS NIH HHS / United States T32 HG000040 / HG / NHGRI NIH HHS / United States R01 HL127564 / HL / NHLBI NIH HHS / United States R01 HL141845 / HL / NHLBI NIH HHS / United States R01 DK075787 / DK / NIDDK NIH HHS / United States R01 AR072199 / AR / NIAMS NIH HHS / United States R01 HL120854 / HL / NHLBI NIH HHS / United States R01 HL163560 / HL / NHLBI NIH HHS / United States R01 HL163972 / HL / NHLBI NIH HHS / United States K23 HL123778 / HL / NHLBI NIH HHS / United States U01 HL137181 / HL / NHLBI NIH HHS / United States R01 MH078111 / MH / NIMH NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States R01 HL141944 / HL / NHLBI NIH HHS / United States R01 HL119443 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States 75N92020D00007 / HL / NHLBI NIH HHS / United States UM1 AI068634 / AI / NIAID NIH HHS / United States HHSN268201500003I / HL / NHLBI NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States F30 HL107066 / HL / NHLBI NIH HHS / United States K01 HL125751 / HL / NHLBI NIH HHS / United States R01 HL067348 / HL / NHLBI NIH HHS / United States T32 HL007208 / HL / NHLBI NIH HHS / United States R01 HL142711 / HL / NHLBI NIH HHS / United States R35 HL135818 / HL / NHLBI NIH HHS / United States T32 GM074897 / GM / NIGMS NIH HHS / United States 75N92020D00001 / HL / NHLBI NIH HHS / United States R01 HL113326 / HL / NHLBI NIH HHS / United States R00 HL129045 / HL / NHLBI NIH HHS / United States U01 HL072524 / HL / NHLBI NIH HHS / United States K08 HL140203 / HL / NHLBI NIH HHS / United States K08 HL141601 / HL / NHLBI NIH HHS / United States R56 AG058543 / AG / NIA NIH HHS / United States U19 AI077439 / AI / NIAID NIH HHS / United States R01 HL142028 / HL / NHLBI NIH HHS / United States 75N92020D00004 / HL / NHLBI NIH HHS / United States HHSN268201800011I / HB / NHLBI NIH HHS / United States R35 GM127131 / GM / NIGMS NIH HHS / United States U01 HL137880 / HL / NHLBI NIH HHS / United States R01 HG010869 / HG / NHGRI NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States R01 HL148239 / HL / NHLBI NIH HHS / United States R01 AI132476 / AI / NIAID NIH HHS / United States T32 GM007205 / GM / NIGMS NIH HHS / United States HHSN268201800010I / HB / NHLBI NIH HHS / United States R01 HL132320 / HL / NHLBI NIH HHS / United States U01 DK078616 / DK / NIDDK NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States U01 HL137162 / HL / NHLBI NIH HHS / United States R01 HL143221 / HL / NHLBI NIH HHS / United States R01 HL142992 / HL / NHLBI NIH HHS / United States K01 HL129039 / HL / NHLBI NIH HHS / United States R01 HL133870 / HL / NHLBI NIH HHS / United States R01 DA037904 / DA / NIDA NIH HHS / United States 75N92020D00002 / HL / NHLBI NIH HHS / United States R21 HL123677 / HL / NHLBI NIH HHS / United States R01 DK071891 / DK / NIDDK NIH HHS / United States K01 HL130609 / HL / NHLBI NIH HHS / United States T32 HL007374 / HL / NHLBI NIH HHS / United States R01 AR063611 / AR / NIAMS NIH HHS / United States R03 HL154284 / HL / NHLBI NIH HHS / United States 75N92020D00006 / HL / NHLBI NIH HHS / United States S10 OD020069 / OD / NIH HHS / United States R01 MD012765 / MD / NIMHD NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States R01 HL151855 / HL / NHLBI NIH HHS / United States F32 HL150992 / HL / NHLBI NIH HHS / United States K23 HL138461 / HL / NHLBI NIH HHS / United States R01 MH101244 / MH / NIMH NIH HHS / United States UM1 DK078616 / DK / NIDDK NIH HHS / United States UG3 HL151865 / HL / NHLBI NIH HHS / United States U01 CA182913 / CA / NCI NIH HHS / United States T32 CA154274 / CA / NCI NIH HHS / United States U01 HG009088 / HG / NHGRI NIH HHS / United States P42 ES016454 / ES / NIEHS NIH HHS / United States P20 GM121334 / GM / NIGMS NIH HHS / United States U01 DK105561 / DK / NIDDK NIH HHS / United States R01 HL131565 / HL / NHLBI NIH HHS / United States R13 CA124365 / CA / NCI NIH HHS / United States P01 HL132825 / HL / NHLBI NIH HHS / United States U54 GM115428 / GM / NIGMS NIH HHS / United States R01 HL118267 / HL / NHLBI NIH HHS / United States HHSN268201800013I / MD / NIMHD NIH HHS / United States R01 HL055673 / HL / NHLBI NIH HHS / United States R01 HL149683 / HL / NHLBI NIH HHS / United States R01 HL092301 / HL / NHLBI NIH HHS / United States P30 DK020595 / DK / NIDDK NIH HHS / United States R01 HL149836 / HL / NHLBI NIH HHS / United States K08 HL145095 / HL / NHLBI NIH HHS / United States K01 HL135405 / HL / NHLBI NIH HHS / United States R03 OD030608 / OD / NIH HHS / United States HHSN268201800014I / HB / NHLBI NIH HHS / United States UM1 AI068636 / AI / NIAID NIH HHS / United States R01 AG057381 / AG / NIA NIH HHS / United States |
A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.
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