New Results
Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
View ORCID ProfileLasse Folkersen, Stefan Gustafsson, Qin Wang, Daniel Hvidberg Hansen, Åsa K Hedman, Andrew Schork, Karen Page, Daria V Zhernakova, Yang Wu, James Peters, Niclas Ericsson, Sarah E Bergen, Thibaud Boutin, View ORCID ProfileAndrew D Bretherick, View ORCID ProfileStefan Enroth, Anettne Kalnapenkis, Jesper R Gådin, Bianca Suur, Yan Chen, Ljubica Matic, Jeremy D Gale, Julie Lee, Weidong Zhang, Amira Quazi, Mika Ala-Korpela, Seung Hoan Choi, Annique Claringbould, John Danesh, George Davey-Smith, Federico de Masi, Sölve Elmståhl, Gunnar Engström, Eric Fauman, Celine Fernandez, Lude Franke, Paul Franks, Vilmantas Giedraitis, Chris Haley, Anders Hamsten, Andres Ingason, View ORCID ProfileÅsa Johansson, View ORCID ProfilePeter K Joshi, Lars Lind, Cecilia M. Lindgren, Steven Lubitz, Tom Palmer, Erin Macdonald-Dunlop, Martin Magnusson, Olle Melander, View ORCID ProfileKarl Michaelsson, Andrew P. Morris, Reedik Mägi, Michael Nagle, Peter M Nilsson, View ORCID ProfileJan Nilsson, Marju Orho-Melander, Ozren Polasek, Bram Prins, Erik Pålsson, Ting Qi, Marketa Sjögren, Johan Sundström, Praveen Surendran, Urmo Võsa, Thomas Werge, Rasmus Wernersson, Harm-Jan Westra, Jian Yang, Alexandra Zhernakova, Johan Ärnlöv, Jingyuan Fu, Gustav Smith, Tonu Esko, Caroline Hayward, Ulf Gyllensten, Mikael Landen, Agneta Siegbahn, Jim F Wilson, Lars Wallentin, Adam S Butterworth, Michael V Holmes, Erik Ingelsson, Anders Mälarstig
doi: https://doi.org/10.1101/2020.04.03.023804
Lasse Folkersen
1Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region, Roskilde, Denmark
2Department of Medicine, Solna, Karolinska Institute, Sweden
Stefan Gustafsson
3Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Qin Wang
4Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
5Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
Daniel Hvidberg Hansen
6Intomics, Lottenborgvej 26, 2800 Lyngby (Copenhagen), Denmark
Åsa K Hedman
2Department of Medicine, Solna, Karolinska Institute, Sweden
7Pfizer Worldwide Research & Development, Cambridge, MA, USA
Andrew Schork
1Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region, Roskilde, Denmark
8Neurogenomics Division, The Translational Genomics Research Institute (TGEN), Phoenix, AZ, USA
Karen Page
9Early Clinical Development, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Daria V Zhernakova
10Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Yang Wu
11Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
James Peters
12BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Niclas Ericsson
13Deparment of Medical Sciences, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
Sarah E Bergen
14Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Thibaud Boutin
15MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland
Andrew D Bretherick
15MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland
Stefan Enroth
16Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-75108 Uppsala, Sweden
Anettne Kalnapenkis
17Estonian Genome Center, Institute of Genomics, University of Tartu 51010, Estonia
Jesper R Gådin
2Department of Medicine, Solna, Karolinska Institute, Sweden
Bianca Suur
18Department of Molecular Medicine and Surgery, Solna, Karolinska Institute, Sweden
Yan Chen
2Department of Medicine, Solna, Karolinska Institute, Sweden
Ljubica Matic
18Department of Molecular Medicine and Surgery, Solna, Karolinska Institute, Sweden
Jeremy D Gale
19Inflammation and Immunology Research Unit, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Julie Lee
9Early Clinical Development, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Weidong Zhang
20Pfizer Global Product Development, Cambridge, MA, USA
Amira Quazi
9Early Clinical Development, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Mika Ala-Korpela
4Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
5Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
21NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Seung Hoan Choi
22Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
Annique Claringbould
10Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
John Danesh
12BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
George Davey-Smith
23MRC Integrative Epidemiology Unit, University of Bristol, UK
Federico de Masi
6Intomics, Lottenborgvej 26, 2800 Lyngby (Copenhagen), Denmark
Sölve Elmståhl
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Gunnar Engström
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Eric Fauman
25Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Celine Fernandez
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Lude Franke
10Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Paul Franks
26Lund University Diabetes Center, Department of Clinical Sciences, Malmö, Sweden
Vilmantas Giedraitis
27Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden
Chris Haley
15MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland
Anders Hamsten
2Department of Medicine, Solna, Karolinska Institute, Sweden
Andres Ingason
1Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region, Roskilde, Denmark
Åsa Johansson
16Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-75108 Uppsala, Sweden
Peter K Joshi
28Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland
Lars Lind
29Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Cecilia M. Lindgren
30Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom
31Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
22Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
Steven Lubitz
32Cardiovascular Research Center, Massachusetts General Hospital, United States
22Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
Tom Palmer
33Department of Mathematics and Statistics, University of Lancaster, Lancaster, UK
Erin Macdonald-Dunlop
28Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland
Martin Magnusson
34Department of Cardiology, Skåne University Hospital Malmö, Malmö, Sweden
35Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
Olle Melander
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Karl Michaelsson
36Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Andrew P. Morris
37Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK
38Department of Biostatistics, University of Liverpool, Liverpool, UK
31Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Reedik Mägi
17Estonian Genome Center, Institute of Genomics, University of Tartu 51010, Estonia
Michael Nagle
25Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Peter M Nilsson
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Jan Nilsson
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Marju Orho-Melander
39Department of Clinical Sciences, Clinical Research Center, Lund University, Malmö, Sweden
Ozren Polasek
40Faculty of Medicine, University of Split, Split, Croatia
Bram Prins
12BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Erik Pålsson
41Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Ting Qi
11Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Marketa Sjögren
24Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Johan Sundström
42Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden; and The George Institute for Global Health, University of New South Wales, Sydney, Australia
Praveen Surendran
12BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Urmo Võsa
17Estonian Genome Center, Institute of Genomics, University of Tartu 51010, Estonia
Thomas Werge
1Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region, Roskilde, Denmark
Rasmus Wernersson
6Intomics, Lottenborgvej 26, 2800 Lyngby (Copenhagen), Denmark
Harm-Jan Westra
10Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Jian Yang
11Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
43Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Alexandra Zhernakova
10Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Johan Ärnlöv
44Department of Neurobiology, Care Sciences and Society (NVS), Division of Family Medicine and Primary Care, Karolinska Institutet, Sweden
Jingyuan Fu
10Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Gustav Smith
45Department of Cardiology, Clinical Sciences, Lund University, Skåne University Hospital, Lund, Sweden
Tonu Esko
17Estonian Genome Center, Institute of Genomics, University of Tartu 51010, Estonia
22Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
Caroline Hayward
15MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland
Ulf Gyllensten
16Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-75108 Uppsala, Sweden
Mikael Landen
41Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Agneta Siegbahn
46Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Jim F Wilson
28Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland
15MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland
Lars Wallentin
47Deparment of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
Adam S Butterworth
12BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Michael V Holmes
48Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Erik Ingelsson
49Department of Medicine, Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, CV 273, Stanford, CA, 94305, USA
Anders Mälarstig
2Department of Medicine, Solna, Karolinska Institute, Sweden
50Emerging Science & Innovation, Pfizer Worldwide Research & Development, Cambridge, MA, USA
Abstract
Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping using trans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Posted April 06, 2020.
Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
Lasse Folkersen, Stefan Gustafsson, Qin Wang, Daniel Hvidberg Hansen, Åsa K Hedman, Andrew Schork, Karen Page, Daria V Zhernakova, Yang Wu, James Peters, Niclas Ericsson, Sarah E Bergen, Thibaud Boutin, Andrew D Bretherick, Stefan Enroth, Anettne Kalnapenkis, Jesper R Gådin, Bianca Suur, Yan Chen, Ljubica Matic, Jeremy D Gale, Julie Lee, Weidong Zhang, Amira Quazi, Mika Ala-Korpela, Seung Hoan Choi, Annique Claringbould, John Danesh, George Davey-Smith, Federico de Masi, Sölve Elmståhl, Gunnar Engström, Eric Fauman, Celine Fernandez, Lude Franke, Paul Franks, Vilmantas Giedraitis, Chris Haley, Anders Hamsten, Andres Ingason, Åsa Johansson, Peter K Joshi, Lars Lind, Cecilia M. Lindgren, Steven Lubitz, Tom Palmer, Erin Macdonald-Dunlop, Martin Magnusson, Olle Melander, Karl Michaelsson, Andrew P. Morris, Reedik Mägi, Michael Nagle, Peter M Nilsson, Jan Nilsson, Marju Orho-Melander, Ozren Polasek, Bram Prins, Erik Pålsson, Ting Qi, Marketa Sjögren, Johan Sundström, Praveen Surendran, Urmo Võsa, Thomas Werge, Rasmus Wernersson, Harm-Jan Westra, Jian Yang, Alexandra Zhernakova, Johan Ärnlöv, Jingyuan Fu, Gustav Smith, Tonu Esko, Caroline Hayward, Ulf Gyllensten, Mikael Landen, Agneta Siegbahn, Jim F Wilson, Lars Wallentin, Adam S Butterworth, Michael V Holmes, Erik Ingelsson, Anders Mälarstig
bioRxiv 2020.04.03.023804; doi: https://doi.org/10.1101/2020.04.03.023804
Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
Lasse Folkersen, Stefan Gustafsson, Qin Wang, Daniel Hvidberg Hansen, Åsa K Hedman, Andrew Schork, Karen Page, Daria V Zhernakova, Yang Wu, James Peters, Niclas Ericsson, Sarah E Bergen, Thibaud Boutin, Andrew D Bretherick, Stefan Enroth, Anettne Kalnapenkis, Jesper R Gådin, Bianca Suur, Yan Chen, Ljubica Matic, Jeremy D Gale, Julie Lee, Weidong Zhang, Amira Quazi, Mika Ala-Korpela, Seung Hoan Choi, Annique Claringbould, John Danesh, George Davey-Smith, Federico de Masi, Sölve Elmståhl, Gunnar Engström, Eric Fauman, Celine Fernandez, Lude Franke, Paul Franks, Vilmantas Giedraitis, Chris Haley, Anders Hamsten, Andres Ingason, Åsa Johansson, Peter K Joshi, Lars Lind, Cecilia M. Lindgren, Steven Lubitz, Tom Palmer, Erin Macdonald-Dunlop, Martin Magnusson, Olle Melander, Karl Michaelsson, Andrew P. Morris, Reedik Mägi, Michael Nagle, Peter M Nilsson, Jan Nilsson, Marju Orho-Melander, Ozren Polasek, Bram Prins, Erik Pålsson, Ting Qi, Marketa Sjögren, Johan Sundström, Praveen Surendran, Urmo Võsa, Thomas Werge, Rasmus Wernersson, Harm-Jan Westra, Jian Yang, Alexandra Zhernakova, Johan Ärnlöv, Jingyuan Fu, Gustav Smith, Tonu Esko, Caroline Hayward, Ulf Gyllensten, Mikael Landen, Agneta Siegbahn, Jim F Wilson, Lars Wallentin, Adam S Butterworth, Michael V Holmes, Erik Ingelsson, Anders Mälarstig
bioRxiv 2020.04.03.023804; doi: https://doi.org/10.1101/2020.04.03.023804
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