Faculty Collaboration Database

cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions. Nat Methods 2026 Feb;23(2):338-349

Date

01/01/2026

Pubmed ID

41476111

Pubmed Central ID

PMC13284854

DOI

10.1038/s41592-025-02919-5

Scopus ID

2-s2.0-105027787046 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Understanding how rare genetic variants influence complex traits remains a major challenge, particularly when these variants lie in noncoding regions of the genome. The effects of variants within candidate cis-regulatory elements (cCREs) often depend on the cell type, making interpretation difficult. Here we introduce cellSTAAR, which integrates whole-genome sequencing data with single-cell assay for transposase-accessible chromatin using sequencing data to capture variability in chromatin accessibility across cell types via the construction of cell-type-specific functional annotations and regulatory elements. To reflect the uncertainty in cCRE-gene linking, cellSTAAR uses a comprehensive strategy to link cCREs to their target genes. We applied cellSTAAR to data from the Trans-Omics for Precision Medicine consortium (n ≈ 60,000) and replicated our findings using the UK Biobank (n ≈ 190,000). Across four lipid traits, cellSTAAR improved the detection of biologically meaningful associations and enhanced biological interpretability. These results demonstrate the potential of cell-type-aware approaches to boost discovery in rare variant whole-genome sequencing association studies.

Author List

Van Buren E, Zhang Y, Li X, Selvaraj MS, Li Z, Zhou H, Palmer ND, Arnett DK, Blangero J, Boerwinkle E, Cade BE, Carlson JC, Carson AP, Chen YI, Curran J, Duggirala R, Fornage M, Franceschini N, Graff M, Gu C, Guo X, He J, Heard-Cosa N, Hou L, Hung YJ, Kalyani RR, Kardia SLR, Kenny E, Kooperberg C, Kral BG, Lange L, Levy D, Li C, Liu S, Lloyd-Jones D, Loos RJF, Manichaikul AW, Martin LW, Mathias R, Minster RL, Mitchell BD, Mychaleckyj JC, Naseri T, North K, O'Connell J, Perry JA, Peyser PA, Psaty BM, Raffield LM, Vasan RS, Redline S, Reiner AP, Rich SS, Smith JA, Spitzer B, Tang H, Taylor KD, Tracy R, Viali S, Yanek L, Zhao W, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Rotter JI, Peloso GM, Natarajan P, Lin X

Authors

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

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

Chromatin
Genetic Variation
Genome, Human
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid
Single-Cell Analysis
Whole Genome Sequencing