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Abstract
Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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1 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
2 Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Center for Primary Care and Public Health, University of Lausanne, Switzerland, Lausanne, Switzerland
3 University Center for Primary Care and Public Health, University of Lausanne, Switzerland, Lausanne, Switzerland; Institute of Computer Science, University of Tartu, Tartu, Estonia
4 Computational Biology, Ontario Institute for Cancer Research, Toronto, ON, Canada
5 Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
6 Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
7 Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
8 Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
9 Heart Center Leipzig, Universität Leipzig, Leipzig, Germany
10 Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK; Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
11 Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
12 Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA
13 Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
14 Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands; Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands
15 Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
16 Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
17 Exeter Medical School, University of Exeter, Exeter, UK
18 Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
19 School of Biological Sciences, Georgia Tech, Atlanta, GA, USA
20 MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
21 Department of Psychiatry and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands
22 Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
23 Centre for Life Course Health Research, University of Oulu, Oulu, Finland
24 Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA; Genetics and Genomic Science Department, Icahn School of Medicine at Mount Sinai, New York, NY, USA
25 Institut für Medizinische Informatik, Statistik und Epidemiologie, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
26 IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany
27 Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany
28 Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
29 Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
30 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; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
31 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
32 National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland
33 Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia
34 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany
35 Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA; Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
36 Centre for Population Health Research, Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital and University of Turku, Turku, Finland
37 Statistical and Translational Genetics, University of Helsinki, Helsinki, Finland
38 DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
39 Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
40 Department of Medicine, Universität Leipzig, Leipzig, Germany
41 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
42 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
43 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
44 Institute for Laboratory Medicine, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany
45 Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
46 Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands
47 Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
48 Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
49 Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia; Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang, China
50 Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
51 SURFsara, Amsterdam, The Netherlands
52 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
53 Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands
54 Department of Genetic Epidemiology, ErasmusMC, Rotterdam, The Netherlands
55 University Center for Primary Care and Public Health, University of Lausanne, Switzerland, Lausanne, Switzerland
56 Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
57 Sequence Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
58 Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
59 Genomics Coordination Center, University Medical Centre Groningen, Groningen, The Netherlands
60 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
61 Endocrine, Diabetes, and Metabolism Service, CHUV and University of Lausanne, Lausanne, Switzerland
62 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland