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The functional impact of rare variation across the regulatory cascade.
Li, Taibo; Ferraro, Nicole; Strober, Benjamin J; Aguet, Francois; Kasela, Silva; Arvanitis, Marios; Ni, Bohan; Wiel, Laurens; Hershberg, Elliot; Ardlie, Kristin; Arking, Dan E; Beer, Rebecca L; Brody, Jennifer; Blackwell, Thomas W; Clish, Clary; Gabriel, Stacey; Gerszten, Robert; Guo, Xiuqing; Gupta, Namrata; Johnson, W Craig; Lappalainen, Tuuli; Lin, Henry J; Liu, Yongmei; Nickerson, Deborah A; Papanicolaou, George; Pritchard, Jonathan K; Qasba, Pankaj; Shojaie, Ali; Smith, Josh; Sotoodehnia, Nona; Taylor, Kent D; Tracy, Russell P; Van Den Berg, David; Wheeler, Matthew T; Rich, Stephen S; Rotter, Jerome I; Battle, Alexis; Montgomery, Stephen B.
Afiliação
  • Li T; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Ferraro N; Biomedical Informatics Training Program, Stanford University, Stanford, CA, USA.
  • Strober BJ; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Aguet F; Harvard School of Public Health, Epidemiology Department, Boston, MA, USA.
  • Kasela S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Arvanitis M; New York Genome Center, New York, NY, USA.
  • Ni B; Department of Systems Biology, Columbia University, New York, NY, USA.
  • Wiel L; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Hershberg E; Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Ardlie K; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
  • Arking DE; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Beer RL; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Brody J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Blackwell TW; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Clish C; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Gabriel S; Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
  • Gerszten R; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • Guo X; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gupta N; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Johnson WC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lappalainen T; Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Lin HJ; 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.
  • Liu Y; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Nickerson DA; Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA.
  • Papanicolaou G; New York Genome Center, New York, NY, USA.
  • Pritchard JK; Department of Systems Biology, Columbia University, New York, NY, USA.
  • Qasba P; 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.
  • Shojaie A; Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
  • Smith J; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Sotoodehnia N; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Taylor KD; Department of Genetics and Biology, Stanford University, Palo Alto, CA, USA.
  • Tracy RP; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Van Den Berg D; Department of Biostatistics, University of Washington School of Public Health, Seattle, WA, USA.
  • Wheeler MT; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Rich SS; Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
  • Rotter JI; 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.
  • Battle A; Laboratory for Clinical Biochemistry Research, University of Vermont, Burlington, VT, USA.
  • Montgomery SB; Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
Cell Genom ; 3(10): 100401, 2023 Oct 11.
Article em En | MEDLINE | ID: mdl-37868038
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cell Genom Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cell Genom Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA