Mendelian randomization for studying the effects of perturbing drug targets.

Drugs Genetics Mendelian randomization

Journal

Wellcome open research
ISSN: 2398-502X
Titre abrégé: Wellcome Open Res
Pays: England
ID NLM: 101696457

Informations de publication

Date de publication:
2021
Historique:
accepted: 01 02 2021
entrez: 2 3 2021
pubmed: 3 3 2021
medline: 3 3 2021
Statut: epublish

Résumé

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.

Identifiants

DOI: 10.12688/wellcomeopenres.16544.2 PMID: 33644404 PMC: PMC7903200
pubmed: 33644404
doi: 10.12688/wellcomeopenres.16544.2
pmc: PMC7903200
doi:

Types de publication

Journal Article Review

Langues

eng

Pagination

16

Subventions

Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : British Heart Foundation
ID : FS/18/23/33512
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/18/50/33837
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/12/2/29428
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00002/7
Pays : United Kingdom
Organisme : VA
ID : PEC 16-001
Pays : United States

Informations de copyright

Copyright: © 2021 Gill D et al.

Déclaration de conflit d'intérêts

Competing interests: DG is employed part-time by Novo Nordisk. DFF is an employee of Bayer AG, Germany. JMMH is an employee of Novo Nordisk. DIS is an employee of Silence Therapeutics plc. MVH has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. RAS is an employee and shareholder in GlaxoSmithKline. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. NMD reports funding from the Global Research Awards into Nicotine Dependence (GRAND) which is an independent grant awarding body funded by Pfizer. All other authors declare no conflicts of interest.

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Auteurs

Dipender Gill (D)

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK.
Novo Nordisk Research Centre, Oxford, UK.
Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, UK.
Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, UK.
ORCID: 0000-0001-7312-7078

Marios K Georgakis (MK)

Institute for Stroke and Dementia Research (ISD), University Hospital of Ludwig-Maximilians-University (LMU), Munich, Germany.

Venexia M Walker (VM)

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0001-5064-446X

A Floriaan Schmidt (AF)

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.

Apostolos Gkatzionis (A)

Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.

Daniel F Freitag (DF)

Bayer Pharmaceuticals, Open Innovation & Digital Technologies, Wuppertal, Germany.

Chris Finan (C)

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.
UCL British Heart Foundation Research Acceleratorversity College London, London, UK.
UCL Hospitals, NIHR Biomedical Research Centre, London, UK.

Aroon D Hingorani (AD)

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.
UCL British Heart Foundation Research Acceleratorversity College London, London, UK.
UCL Hospitals, NIHR Biomedical Research Centre, London, UK.

Joanna M M Howson (JMM)

Novo Nordisk Research Centre, Oxford, UK.

Stephen Burgess (S)

Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
ORCID: 0000-0001-5365-8760

Daniel I Swerdlow (DI)

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.

George Davey Smith (G)

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
NIHR Bristol Biomedical Research Centre, University of Bristol, Bristol, UK.
ORCID: 0000-0002-1407-8314

Michael V Holmes (MV)

Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
ORCID: 0000-0001-6617-0879

Martin Dichgans (M)

Institute for Stroke and Dementia Research (ISD), University Hospital of Ludwig-Maximilians-University (LMU), Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.

Robert A Scott (RA)

Human Genetics, GlaxoSmithKline, Stevenage, UK.

Jie Zheng (J)

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Bruce M Psaty (BM)

Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
ORCID: 0000-0002-7278-2190

Neil M Davies (NM)

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
ORCID: 0000-0002-2460-0508

Classifications MeSH