A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies

Z Li, X Li, H Zhou, SM Gaynor, MS Selvaraj… - Nature …, 2022 - nature.com
Z Li, X Li, H Zhou, SM Gaynor, MS Selvaraj, T Arapoglou, C Quick, Y Liu, H Chen, R Sun
Nature methods, 2022nature.com
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 …
Abstract
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.
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