Medical College of Wisconsin
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A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies. Nat Comput Sci 2025 Feb;5(2):125-143

Date

02/08/2025

Pubmed ID

39920506

Pubmed Central ID

PMC11981678

DOI

10.1038/s43588-024-00764-8

Scopus ID

2-s2.0-105010391903 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

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.

Author List

Li X, Chen H, Selvaraj MS, Van Buren E, Zhou H, Wang Y, Sun R, McCaw ZR, Yu Z, Jiang MZ, 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 YI, Curran JE, de Vries PS, Fornage M, Franceschini N, Freedman BI, Gu C, Heard-Costa NL, He J, Hou L, Hung YJ, Irvin MR, Kaplan RC, Kardia SLR, Kelly TN, Konigsberg I, Kooperberg C, Kral BG, Li C, Li Y, Lin H, Liu CT, 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, Wang Z, Wessel J, Yanek LR, Yu B, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Dupuis J, Meigs JB, Auer PL, Raffield LM, Manning AK, Rice KM, Rotter JI, Peloso GM, Natarajan P, Li Z, Liu Z, Lin X

Author

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Genetic Variation
Genome, Human
Genome-Wide Association Study
Humans
Phenotype
Whole Genome Sequencing