A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies

Xihao Li, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Han Chen, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Margaret Sunitha Selvaraj, Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Eric Van Buren, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Hufeng Zhou, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Yuxuan Wang, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Ryan Sun, Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Zachary R. McCaw, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Zhi Yu, Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Donna K. Arnett, Provost Office, University of South Carolina, Columbia, SC, USA.
Joshua C. Bis, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
John Blangero, Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.
Eric Boerwinkle, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Donald W. Bowden, Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Jennifer A. Brody, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Brian E. Cade, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
April P. Carson, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Jenna C. Carlson, Department of Human Genetics and Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
Nathalie Chami, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Yii-Der Ida Chen, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Joanne E. Curran, Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.
Paul S. de Vries, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Myriam Fornage, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Nora Franceschini, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Barry I. Freedman, Department of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Charles Gu, Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
Nancy L. Heard-Costa, Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Jiang He, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
Lifang Hou, Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Yi-Jen Hung, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Marguerite R. Irvin, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Robert C. Kaplan, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Document Type

Journal Article

Publication Date

11-2-2023

Journal

bioRxiv : the preprint server for biology

DOI

10.1101/2023.10.30.564764

Abstract

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

Department

Medicine

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