Journal
NATURE METHODS
Volume 19, Issue 12, Pages 1599-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41592-022-01640-x
Keywords
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Categories
Funding
- Evans Medical Foundation
- Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine
- NHLBI
- TOPMed Informatics Research Center [3R01HL-117626-02S1, HHSN268201800002I]
- TOPMed Data Coordinating Center [HHSN268201800001I, R01HL-120393, U01HL-120393]
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Ask authors/readers for more resources
Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant associations with complex human diseases and traits. The proposed STAARpipeline is a computationally efficient and robust framework for noncoding rare-variant association analysis. It can automatically annotate whole-genome sequencing data and perform flexible gene-centric and non-gene-centric analysis by incorporating multiple functional annotations.
Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits. STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.
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