1. A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies
- Author
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Li, Zilin, Li, Xihao, Zhou, Hufeng, Gaynor, Sheila M, Selvaraj, Margaret Sunitha, Arapoglou, Theodore, Quick, Corbin, Liu, Yaowu, Chen, Han, Sun, Ryan, Dey, Rounak, Arnett, Donna K, Auer, Paul L, Bielak, Lawrence F, Bis, Joshua C, Blackwell, Thomas W, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Conomos, Matthew P, Correa, Adolfo, Cupples, L Adrienne, Curran, Joanne E, de Vries, Paul S, Duggirala, Ravindranath, Franceschini, Nora, Freedman, Barry I, Göring, Harald HH, Guo, Xiuqing, Kalyani, Rita R, Kooperberg, Charles, Kral, Brian G, Lange, Leslie A, Lin, Bridget M, Manichaikul, Ani, Manning, Alisa K, Martin, Lisa W, Mathias, Rasika A, Meigs, James B, Mitchell, Braxton D, Montasser, May E, Morrison, Alanna C, Naseri, Take, O’Connell, Jeffrey R, Palmer, Nicholette D, Peyser, Patricia A, Psaty, Bruce M, Raffield, Laura M, Redline, Susan, Reiner, Alexander P, Reupena, Muagututi’a Sefuiva, Rice, Kenneth M, Rich, Stephen S, Smith, Jennifer A, Taylor, Kent D, Taub, Margaret A, Vasan, Ramachandran S, Weeks, Daniel E, Wilson, James G, Yanek, Lisa R, Zhao, Wei, Rotter, Jerome I, Willer, Cristen J, Natarajan, Pradeep, Peloso, Gina M, and Lin, Xihong
- Subjects
Biological Sciences ,Genetics ,Precision Medicine ,Biotechnology ,Human Genome ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Humans ,Genome-Wide Association Study ,Whole Genome Sequencing ,Genome ,Phenotype ,Genetic Variation ,NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ,TOPMed Lipids Working Group ,Technology ,Medical and Health Sciences ,Developmental Biology ,Biological sciences - 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.
- Published
- 2022