cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions
- 31 December 2025
- journal article
- research article
- Published by Springer Nature in Nature Methods
- Vol. 23 (2) , 338-349
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.Keywords
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Funding Information
- National Cancer Institute (R35-CA197449)
- National Cancer Institute (U19-CA203654)
- National Human Genome Research Institute (U01-HG012064)
- National Human Genome Research Institute (U01-HG009088)
- National Heart, Lung, and Blood Institute (R01HL173044)
- National Heart, Lung, and Blood Institute (75N92021F00229)
- National Heart, Lung, and Blood Institute (75N92021F00229)
- National Heart, Lung, and Blood Institute (U01- HL072524)
- National Heart, Lung, and Blood Institute (R01-HL104135-04S1)
- National Heart, Lung, and Blood Institute (U01-HL054472)
- National Heart, Lung, and Blood Institute (U01-HL054473)
- National Heart, Lung, and Blood Institute (U01-HL054495)
- National Heart, Lung, and Blood Institute (U01-HL054509)
- National Heart, Lung, and Blood Institute (R01-HL055673-18S1)
- National Heart, Lung, and Blood Institute (HHSN268201700001I)
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- National Heart, Lung, and Blood Institute (75N92020D00001)
- National Heart, Lung, and Blood Institute (HHSN268201500003I)
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- National Heart, Lung, and Blood Institute (N01-HC-95165)
- National Heart, Lung, and Blood Institute (N01-HC-95166)
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- National Heart, Lung, and Blood Institute (HHSN268201600018C)
- National Heart, Lung, and Blood Institute (HHSN268201600001C)
- National Heart, Lung, and Blood Institute (HHSN268201600002C)
- National Heart, Lung, and Blood Institute (HHSN268201600003C)
- National Heart, Lung, and Blood Institute (HHSN268201600004C)
- National Heart, Lung, and Blood Institute (HL105756)
- National Heart, Lung, and Blood Institute (1R35-HL135818)
- National Heart, Lung, and Blood Institute (R01- HL113338)
- National Heart, Lung, and Blood Institute (HL046389)
- National Heart, Lung, and Blood Institute (75N92020D00001)
- National Heart, Lung, and Blood Institute (HHSN268201500003I)
- National Heart, Lung, and Blood Institute (N01-HC-95159)
- National Heart, Lung, and Blood Institute (75N92020D00003)
- National Heart, Lung, and Blood Institute (N01-HC-95162)
- National Heart, Lung, and Blood Institute (75N92020D00006)
- National Heart, Lung, and Blood Institute (N01-HC-95163)
- National Heart, Lung, and Blood Institute (75N92020D00004)
- National Heart, Lung, and Blood Institute (N01-HC-95164)
- National Heart, Lung, and Blood Institute (75N92020D00007)
- National Heart, Lung, and Blood Institute (N01-HC-95165)
- National Heart, Lung, and Blood Institute (N01-HC-95166)
- National Heart, Lung, and Blood Institute (N01-HC-95167)
- National Heart, Lung, and Blood Institute (N01-HC-95168)
- National Heart, Lung, and Blood Institute (N01-HC-95169)
- National Heart, Lung, and Blood Institute (R01-HL071051)
- National Heart, Lung, and Blood Institute (R01-HL071205)
- National Heart, Lung, and Blood Institute (R01- HL071250)
- National Heart, Lung, and Blood Institute (R01-HL071251)
- National Heart, Lung, and Blood Institute (R01-HL071258)
- National Heart, Lung, and Blood Institute (R01-HL071259)
- National Heart, Lung, and Blood Institute (R01-HL142711)
- National Heart, Lung, and Blood Institute (R01-HL127564)
- National Heart, Lung, and Blood Institute (R01-HL142711)
- National Heart, Lung, and Blood Institute (R01-HL127564)
- National Center for Advancing Translational Sciences (UL1-TR-000040)
- National Center for Advancing Translational Sciences (UL1-TR-001079)
- National Center for Advancing Translational Sciences (UL1-TR-001420)
- National Center for Advancing Translational Sciences (UL1-TR001881)
- National Center for Advancing Translational Sciences (UL1-TR-000040)
- National Center for Advancing Translational Sciences (UL1-TR-001079)
- National Center for Advancing Translational Sciences (UL1-TR-001420)
- National Center for Advancing Translational Sciences (UL1-TR001881)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK117445)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491)
- National Center for Research Resources (UL1-RR033176)
- National Center for Research Resources (UL1-RR033176)
- National Institute on Minority Health and Health Disparities (R01-MD012765)
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