| Title: | cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions |
| Journal: | Nature Methods |
| Published: | 31 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41476111/ |
| DOI: | https://doi.org/10.1038/s41592-025-02919-5 |
Publication 16939
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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.</p>
65 Authors
- Eric Van Buren
- Yi Zhang
- Xihao Li
- Margaret Sunitha Selvaraj
- Zilin Li
- Hufeng Zhou
- Nicholette D. Palmer
- Donna K. Arnett
- John Blangero
- Eric Boerwinkle
- Brian E. Cade
- Jenna C. Carlson
- April P. Carson
- Yii-Der Ida Chen
- Joanne Curran
- Ravindranath Duggirala
- Myriam Fornage
- Nora Franceschini
- Misa Graff
- Charles Gu
- Xiuqing Guo
- Jiang He
- Nancy Heard-Cosa
- Lifang Hou
- Yi-Jen Hung
- Rita R. Kalyani
- Sharon L. R. Kardia
- Eimear Kenny
- Charles Kooperberg
- Brian G. Kral
- Leslie Lange
- Dan Levy
- Changwei Li
- Simin Liu
- Donald Lloyd-Jones
- Ruth J. F. Loos
- Ani W. Manichaikul
- Lisa Warsinger Martin
- Rasika Mathias
- Ryan L. Minster
- Braxton D. Mitchell
- Josyf C. Mychaleckyj
- Take Naseri
- Kari North
- Jeff O'Connell
- James A. Perry
- Patricia A. Peyser
- Bruce M. Psaty
- Laura M. Raffield
- Ramachandran S. Vasan
- Susan Redline
- Alex P. Reiner
- Stephen S. Rich
- Jennifer A. Smith
- Brian Spitzer
- Hua Tang
- Kent D. Taylor
- Russell Tracy
- Satupa'itea Viali
- Lisa Yanek
- Wei Zhao
- Jerome I. Rotter
- Gina M. Peloso
- Pradeep Natarajan
- Xihong Lin
1 Application
| Application ID | Title |
|---|---|
| 52008 | Development of statistical methods to discover novel genetic associations, explain underlying biological mechanisms, and develop risk prediction models across varied complex diseases. |
Enabling scientific discoveries that improve human health