Faculty, Staff and Student Publications

Language

English

Publication Date

2-1-2026

Journal

Nature Methods

DOI

10.1038/s41592-025-02919-5

PMID

41476111

PMCID

PMC13284854

PubMedCentral® Posted Date

6-23-2026

PubMedCentral® Full Text Version

Author MSS

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

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

Published Open-Access

yes

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