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A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.
Tuesday,2025-04-08 13:36 America/Los_Angeles — ecterry
| Title | A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies. |
| Publication Type | Journal Article |
| Year of Publication | 2025 |
| Authors | Li, X, Chen, H, Selvaraj, MSunitha, Van Buren, E, Zhou, H, Wang, Y, Sun, R, McCaw, ZR, Yu, Z, Jiang, M-Z, DiCorpo, D, Gaynor, SM, Dey, R, Arnett, DK, Benjamin, EJ, Bis, JC, Blangero, J, Boerwinkle, E, Bowden, DW, Brody, JA, Cade, BE, Carson, AP, Carlson, JC, Chami, N, Chen, Y-DI, Curran, JE, de Vries, PS, Fornage, M, Franceschini, N, Freedman, BI, Gu, C, Heard-Costa, NL, He, J, Hou, L, Hung, Y-J, Irvin, MR, Kaplan, RC, Kardia, SLR, Kelly, TN, Konigsberg, I, Kooperberg, C, Kral, BG, Li, C, Li, Y, Lin, H, Liu, C-T, Loos, RJF, Mahaney, MC, Martin, LW, Mathias, RA, Mitchell, BD, Montasser, ME, Morrison, AC, Naseri, T, North, KE, Palmer, ND, Peyser, PA, Psaty, BM, Redline, S, Reiner, AP, Rich, SS, Sitlani, CM, Smith, JA, Taylor, KD, Tiwari, HK, Vasan, RS, Viali, S'itea, Wang, Z, Wessel, J, Yanek, LR, Yu, B, Dupuis, J, Meigs, JB, Auer, PL, Raffield, LM, Manning, AK, Rice, KM, Rotter, JI, Peloso, GM, Natarajan, P, Li, Z, Liu, Z, Lin, X |
| Corporate/Institutional Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |
| Journal | Nat Comput Sci |
| Volume | 5 |
| Issue | 2 |
| Pagination | 125-143 |
| Date Published | 2025 Feb |
| ISSN | 2662-8457 |
| Keywords | Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Lipids, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Whole Genome Sequencing |
| Abstract | <p>Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.</p> |
| DOI | 10.1038/s43588-024-00764-8 |
| Alternate Journal | Nat Comput Sci |
| PubMed ID | 39920506 |
| Grant List | N01-HC-95166 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / UL1-TR001881 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / HHSN268201700003I / HL / NHLBI NIH HHS / United States K26 DK138425 / DK / NIDDK NIH HHS / United States R01 HL113323 / HL / NHLBI NIH HHS / United States U01-HG012064 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) / N01-HC-95160 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01-HL071251 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / HHSN268201600002C / HL / NHLBI NIH HHS / United States R01-DK117445 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01 HL120393 / HL / NHLBI NIH HHS / United States 75N92020D00003 / HL / NHLBI NIH HHS / United States U01 DK085524 / DK / NIDDK NIH HHS / United States N01-HC-95163 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / U19 CA203654 / CA / NCI NIH HHS / United States R01-HL071259 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01 HL175681 / HL / NHLBI NIH HHS / United States U01 HG012064 / HG / NHGRI NIH HHS / United States N01-HC-95169 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / DK063491 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01-HL071205 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01 HL092577 / HL / NHLBI NIH HHS / United States R01 HL113338 / HL / NHLBI NIH HHS / United States R01 DK117445 / DK / NIDDK NIH HHS / United States R01-HL104135-04S1 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / UL1-TR-000040 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / N01-HC-95162 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / N01-HC-95167 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01-HL113338 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / R01 HL163972 / HL / NHLBI NIH HHS / United States HHSN268201600004C / HL / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States R03-HL154284 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / R01-HL142711 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / NHLBI TOPMed Fellowship 75N92021F00229 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / 75N92020D00007 / HL / NHLBI NIH HHS / United States HHSN268201500003I / HL / NHLBI NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States R01-HL071051 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / 1R01AG086379-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01-HL071250 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / 75N92020D00001 / HL / NHLBI NIH HHS / United States R35-CA197449 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / DK078616 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / 75N92020D00005 / HL / NHLBI NIH HHS / United States HHSN268201800001I / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / N01-HC-95161 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / 75N92020D00004 / HL / NHLBI NIH HHS / United States U01-HG009088 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) / HL046389 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / U19-CA203654 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / N01-HC-95168 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / HHSN268201700001I / HL / NHLBI NIH HHS / United States 1R35-HL135818 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / U01 HL137162 / HL / NHLBI NIH HHS / United States U54 HG013247 / HG / NHGRI NIH HHS / United States 75N92020D00002 / HL / NHLBI NIH HHS / United States HHSN268201600018C / HL / NHLBI NIH HHS / United States R01 HG013163 / HG / NHGRI NIH HHS / United States R01-MD012765 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R00HG012956-02 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) / 75N92020D00006 / HL / NHLBI NIH HHS / United States HL105756 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / U01-HL054472 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / HHSN268201700002I / HL / NHLBI NIH HHS / United States U01 HG009088 / HG / NHGRI NIH HHS / United States N01-HC-95159 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / HHSN268201600001C / HL / NHLBI NIH HHS / United States U01-HL054473 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / N01-HC-95164 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / UL1-TR-001079 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / U01-HL054509 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / UL1-TR-001420 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / U01-HL054495 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / U01-HL137162 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / R01-HL071258 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / HHSN268201600003C / HL / NHLBI NIH HHS / United States UL1-RR033176 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / N01-HC-95165 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01-HL153805 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / R01-HL055673-18S1 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / HL151855 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / R01-HL127564 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / U01-HL072524 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / |
ePub date:
25/02