OTTERS: a powerful TWAS framework leveraging summary-level reference data
Nature Communications, vol. 14, pp. 1271
Abstract
Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
Authors 85
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Affiliation as printed
Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA, 30322, USA
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Affiliation as printed
Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06511, USA
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Affiliation as printed
Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06520, USA
Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06511, USA
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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University Medical Center Groningen · University of Groningen · Oncode Institute
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
Oncode Institute, 3521 AL, Utrecht, The Netherlands
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Affiliation as printed
Department of Computer Science, and Departments of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
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Universitätsmedizin Greifswald · Universität Greifswald
Affiliation as printed
Institute for Community Medicine, University Medicine Greifswald, 17489, Greifswald, Germany
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Tampere University · Fimlab (Finland) · University of Tampere
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Centre for Cardiovascular Disease Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland
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University of Turku · Turku University Hospital
Affiliation as printed
Centre for Population Health Research, University of Turku and Turku University Hospital, 20520, Turku, Finland
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521, Turku, Finland
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520, Turku, Finland
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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Ontario Institute for Cancer Research
Affiliation as printed
Computational Biology, Ontario Institute for Cancer Research, Toronto, ON, Canada
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Affiliation as printed
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
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Ontario Institute for Cancer Research
Affiliation as printed
Computational Biology, Ontario Institute for Cancer Research, Toronto, ON, Canada
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Agency for Science, Technology and Research · Singapore Immunology Network
Affiliation as printed
Singapore Immunology Network, Agency for Science Technology and Research, Singapore, Singapore
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Wibowo Arindrarto Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden, The Netherlands
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Ontario Institute for Cancer Research
Affiliation as printed
Computational Biology, Ontario Institute for Cancer Research, Toronto, ON, Canada
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Affiliation as printed
Heart Center Leipzig, Universität Leipzig, Leipzig, Germany
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University Medical Center Groningen · University of Groningen · European Molecular Biology Laboratory
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, Germany
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Affiliation as printed
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
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University Medical Center Groningen · University of Groningen · Oncode Institute
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
Oncode Institute, 3521 AL, Utrecht, The Netherlands
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University Medical Center Groningen · University of Groningen · University Medical Center Utrecht · Oncode Institute
Affiliation as printed
Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands
Oncode Institute, 3521 AL, Utrecht, The Netherlands
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Ontario Institute for Cancer Research
Affiliation as printed
Computational Biology, Ontario Institute for Cancer Research, Toronto, ON, Canada
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University of Exeter · Royal Devon and Exeter Hospital · Exeter Hospital
Affiliation as printed
Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
Department of Medicine, University of Washington, Seattle, WA, USA
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Georgia Institute of Technology
Affiliation as printed
School of Biological Sciences, Georgia Tech, Atlanta, GA, USA
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Bastiaan T. Heijmans Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden, The Netherlands
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University of Bristol · MRC Integrative Epidemiology Unit
Affiliation as printed
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
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Amsterdam University Medical Centers · Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Tampere University · Tampere University Hospital · University of Tampere
Affiliation as printed
Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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Affiliation as printed
University of Helsinki, Helsinki, Finland
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Johns Hopkins University · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Computer Science, and Departments of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
Genetics and Genomic Science Department, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Affiliation as printed
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
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IFB Adiposity Diseases · Leipzig University
Affiliation as printed
IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany
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Affiliation as printed
Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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Centre Hospitalier Universitaire Vaudois
Affiliation as printed
Lausanne University Hospital, Lausanne, Switzerland
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Agency for Science, Technology and Research · Singapore Immunology Network
Affiliation as printed
Singapore Immunology Network, Agency for Science Technology and Research, Singapore, Singapore
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Affiliation as printed
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
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Ikerbasque · Georgia Institute of Technology · Euskadiko Parke Teknologikoa · CIC bioGUNE
Affiliation as printed
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Integrative Genomics Lab, CIC bioGUNE, Bizkaia Science and Technology Park, Derio, Bizkaia, Basque Country, Spain
School of Biological Sciences, Georgia Tech, Atlanta, GA, USA
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Leiden University Medical Center
Affiliation as printed
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
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Helmholtz Munich · German Centre for Cardiovascular Research · Ludwig-Maximilians-Universität München
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
Department of Medicine I, University Hospital Munich, Ludwig Maximilian’s University, München, Germany
Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
Department of Medicine I, University Hospital Munich, Ludwig Maximilian's University, München, Germany
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Universitätsmedizin Greifswald · German Centre for Cardiovascular Research
Affiliation as printed
German Center for Cardiovascular Research (partner site Greifswald), Greifswald, Germany
Institute of Clinical Chemistry and Laboratory Medicine, Greifswald University Hospital, Greifswald, Germany
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Affiliation as printed
Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, VU, Amsterdam, The Netherlands
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Amsterdam University Medical Centers · Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Affiliation as printed
National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, 50090, Tartu, Estonia
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Affiliation as printed
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
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Garvan Institute of Medical Research
Affiliation as printed
Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, NSW, Australia
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Helmholtz Munich · Institut für Humangenetik · Technical University of Munich
Affiliation as printed
Institute of Human Genetics, Technical University Munich, Munich, Germany
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany
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Kaiser Permanente Washington Health Research Institute · University of Washington
Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
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Affiliation as printed
Statistical and Translational Genetics, University of Helsinki, Helsinki, Finland
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Agency for Science, Technology and Research · Singapore Immunology Network
Affiliation as printed
Singapore Immunology Network, Agency for Science Technology and Research, Singapore, Singapore
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Centre Hospitalier Universitaire Vaudois
Affiliation as printed
Lausanne University Hospital, Lausanne, Switzerland
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Affiliation as printed
Department of Computer Science, and Departments of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
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Affiliation as printed
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
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Helmholtz Munich · Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Medicine I, University Hospital Munich, Ludwig Maximilian’s University, München, Germany
Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
Department of Medicine I, University Hospital Munich, Ludwig Maximilian's University, München, Germany
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Tampere University · Fimlab (Finland) · University of Tampere
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Centre for Cardiovascular Disease Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland
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P. Eline Slagboom Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden, The Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
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Affiliation as printed
Department of Medicine, Universität Leipzig, Leipzig, Germany
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
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Affiliation as printed
Institute for Laboratory Medicine, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
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Affiliation as printed
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
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German Centre for Cardiovascular Research
Affiliation as printed
German Center for Cardiovascular Research (partner site Greifswald), Greifswald, Germany
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Affiliation as printed
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Maarten van Iterson Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht University, Utrecht, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
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The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
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Universitätsmedizin Greifswald · Universität Greifswald
Affiliation as printed
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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University Medical Center Groningen · University of Groningen · Oncode Institute
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
Oncode Institute, 3521 AL, Utrecht, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
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Luleå University of Technology · University of Exeter · Royal Devon and Exeter Hospital · Exeter Hospital · University of Westminster
Affiliation as printed
Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK
School of Life Sciences, College of Liberal Arts and Science, University of Westminster, 115 New Cavendish Street, London, UK
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Jian Yang corresponding
Emory University · The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. jingjing.yang@emory.edu
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
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Emory University · The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
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Michael P. Epstein corresponding
Affiliation as printed
Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. mpepste@emory.edu
Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
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Jingjing Yang corresponding
Affiliation as printed
Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. jingjing.yang@emory.edu
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