MR-link-2: pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality
Nature Communications, vol. 16, pp. 6112
Abstract
Abstract Mendelian randomization (MR) can identify causal relationships from observational data but has increased Type 1 error rates (T1E) when genetic instruments are limited to a single associated region, a typical scenario for molecular exposures. To address this, we developed MR-link-2, which uses summary statistics and linkage disequilibrium (LD) information to simultaneously estimate a causal effect and pleiotropy in a single associated region. We extensively compare MR-link-2 to other cis MR methods: i) In realistic simulations, MR-link-2 has calibrated T1E and high power. ii) We replicate causal relationships derived from three metabolic pathway references using four independent metabolite quantitative trait locus studies as input to MR. Compared to other methods, MR-link-2 has a superior area under the receiver operator characteristic curve (AUC) (up to 0.80). iii) Applied to canonical causal relationships between complex traits, MR-link-2 has a lower per-locus T1E rate than competing methods (0.09 vs 0.15, at a nominal 5% level) and has several fold less heterogeneous causal effect estimates. iv) Testing the correct causal direction between blood cell type compositions and gene expression of their marker genes reveals that MR-link has superior AUC 0.90 (best competing: 0.67). Finally, when testing for causality between metabolites that are not connected by canonical reactions, MR-link-2 exclusively identifies a link between glycine and pyrroline-5-carboxylate, corroborating results for hypomyelinating leukodystrophy-10, otherwise only found in model systems. Overall, MR-link-2 is the first method to identify pleiotropy-robust causality from summary statistics in single associated regions, making it ideally suited for applications on molecular phenotypes.
Authors 32
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SIB Swiss Institute of Bioinformatics · University of Lausanne
Affiliation as printed
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
Swiss Institute of Bioinformatics, Lausanne, Switzerland
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University of Groningen · Oncode Institute
Affiliation as printed
Department of Genetics, University of Groningen, Groningen, The Netherlands
Oncode institute, Utrecht, The Netherlands
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SIB Swiss Institute of Bioinformatics · University of Lausanne
Affiliation as printed
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
Swiss Institute of Bioinformatics, Lausanne, Switzerland
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University of Bristol · Amsterdam Public Health · MRC Integrative Epidemiology Unit · Amsterdam Reproduction Development · Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Public Health research institute, Amsterdam, the Netherlands
Amsterdam Reproduction & Development (AR&D) research institute, Amsterdam, the Netherlands
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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SIB Swiss Institute of Bioinformatics · The University of Queensland · Institute for Molecular Bioscience · University of Lausanne
Affiliation as printed
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. Zoltan.Kutalik@unil.ch
Swiss Institute of Bioinformatics, Lausanne, Switzerland. Zoltan.Kutalik@unil.ch
University Center for Primary Care and Public Health, Lausanne, Switzerland. Zoltan.Kutalik@unil.ch
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Affiliation as printed
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Affiliation as printed
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
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Affiliation as printed
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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Georgia Institute of Technology
Affiliation as printed
Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, USA
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Affiliation as printed
CARIM, Maastricht University, Maastricht, The Netherlands
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Affiliation as printed
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Tampere University · Tampere University Hospital · University of Tampere
Affiliation as printed
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Tampere University · Fimlab (Finland) · University of Tampere
Affiliation as printed
Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Affiliation as printed
Unit of Genomic of Complex Diseases, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
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The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
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The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
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University of California, Los Angeles
Affiliation as printed
Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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University of California, Los Angeles
Affiliation as printed
Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA
Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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AstraZeneca (United Kingdom) · University of Cambridge
Affiliation as printed
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
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Affiliation as printed
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
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Helmholtz Munich · German Centre for Cardiovascular Research · German Center for Diabetes Research · Ludwig-Maximilians-Universität München
Affiliation as printed
Chair of Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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Helmholtz Munich · Institut für Humangenetik · Technical University of Munich
Affiliation as printed
German Center for Child and Adolescent Health (DZKJ), partner site Munich, Munich, Germany
Institute of Neurogenomics, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
School of Medicine, Institute of Human Genetics, Technical University of Munich, Munich, Germany
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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, Turku, Finland
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
InFLAMES Research Flagship, University of Turku, Turku, Finland
Research centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
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National Institutes of Health · National Institute on Aging
Affiliation as printed
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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Leiden University Medical Center
Affiliation as printed
Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Unit of Genomic of Complex Diseases, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Neurology, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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The University of Queensland · Institute for Molecular Bioscience
Affiliation as printed
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
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Universitätsmedizin Greifswald · Universität Greifswald · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Strasse 8, Greifswald, Germany
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University of Groningen · Oncode Institute
Affiliation as printed
Department of Genetics, University of Groningen, Groningen, The Netherlands
Oncode institute, Utrecht, The Netherlands
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University of Groningen · Oncode Institute
Affiliation as printed
Department of Genetics, University of Groningen, Groningen, The Netherlands
Oncode institute, Utrecht, The Netherlands
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