Cell Genomics (Oct 2023)
The functional impact of rare variation across the regulatory cascade
- Taibo Li,
- Nicole Ferraro,
- Benjamin J. Strober,
- Francois Aguet,
- Silva Kasela,
- Marios Arvanitis,
- Bohan Ni,
- Laurens Wiel,
- Elliot Hershberg,
- Kristin Ardlie,
- Dan E. Arking,
- Rebecca L. Beer,
- Jennifer Brody,
- Thomas W. Blackwell,
- Clary Clish,
- Stacey Gabriel,
- Robert Gerszten,
- Xiuqing Guo,
- Namrata Gupta,
- W. Craig Johnson,
- Tuuli Lappalainen,
- Henry J. Lin,
- Yongmei Liu,
- Deborah A. Nickerson,
- George Papanicolaou,
- Jonathan K. Pritchard,
- Pankaj Qasba,
- Ali Shojaie,
- Josh Smith,
- Nona Sotoodehnia,
- Kent D. Taylor,
- Russell P. Tracy,
- David Van Den Berg,
- Matthew T. Wheeler,
- Stephen S. Rich,
- Jerome I. Rotter,
- Alexis Battle,
- Stephen B. Montgomery
Affiliations
- Taibo Li
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Nicole Ferraro
- Biomedical Informatics Training Program, Stanford University, Stanford, CA, USA
- Benjamin J. Strober
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Harvard School of Public Health, Epidemiology Department, Boston, MA, USA
- Francois Aguet
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Silva Kasela
- New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA
- Marios Arvanitis
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Bohan Ni
- Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
- Laurens Wiel
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Elliot Hershberg
- Department of Genetics, Stanford University, Stanford, CA, USA
- Kristin Ardlie
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Dan E. Arking
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Rebecca L. Beer
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Jennifer Brody
- Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA
- Thomas W. Blackwell
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
- Clary Clish
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stacey Gabriel
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Robert Gerszten
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Xiuqing Guo
- 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
- Namrata Gupta
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- W. Craig Johnson
- Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA
- Tuuli Lappalainen
- New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA
- Henry J. Lin
- 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
- Yongmei Liu
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Deborah A. Nickerson
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- George Papanicolaou
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Jonathan K. Pritchard
- Department of Genetics and Biology, Stanford University, Palo Alto, CA, USA
- Pankaj Qasba
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Ali Shojaie
- Department of Biostatistics, University of Washington School of Public Health, Seattle, WA, USA
- Josh Smith
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Nona Sotoodehnia
- Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA
- Kent D. Taylor
- 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
- Russell P. Tracy
- Laboratory for Clinical Biochemistry Research, University of Vermont, Burlington, VT, USA
- David Van Den Berg
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
- Matthew T. Wheeler
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Jerome I. Rotter
- 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
- Alexis Battle
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Malone Center for Engineering of Healthcare, Johns Hopkins University, Baltimore, MD, USA; Corresponding author
- Stephen B. Montgomery
- Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Corresponding author
- Journal volume & issue
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Vol. 3,
no. 10
p. 100401
Abstract
Summary: Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype’s ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13–27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, “Watershed,” to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer’s disease.
