Common pitfalls in drug target Mendelian randomization and how to avoid them

Dipender Gill; Marie-Joe Dib; Héléne T Cronjé; Ville Karhunen; Benjamin Woolf; Eloi Gagnon; Iyas Daghlas; Michael Nyberg; Donald Drakeman; Stephen Burgess

doi:10.1186/s12916-024-03700-9

Common pitfalls in drug target Mendelian randomization and how to avoid them

BMC Med. 2024 Oct 15;22(1):473. doi: 10.1186/s12916-024-03700-9.

Authors

Dipender Gill^{1

2}, Marie-Joe Dib³, Héléne T Cronjé^{4

5}, Ville Karhunen^{4

5}, Benjamin Woolf^{5

6

7}, Eloi Gagnon⁸, Iyas Daghlas⁹, Michael Nyberg¹⁰, Donald Drakeman^{11

12}, Stephen Burgess^{4

5

13}

Affiliations

¹ Sequoia Genetics, London, UK. [email protected].
² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, 90 Wood Lane, London, W12 0BZ, UK. [email protected].
³ Cardiovascular Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
⁴ Sequoia Genetics, London, UK.
⁵ Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁶ School of Psychological Science, University of Bristol, Bristol, UK.
⁷ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁸ Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec, Canada.
⁹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Cardiovascular Biology, Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark.
¹¹ University of Cambridge Centre for Health Leadership & Enterprise, Judge Business School, Trumpington Street, Cambridge, UK.
¹² Advent Venture Partners, London, UK.
¹³ Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Abstract

Background: Drug target Mendelian randomization describes the use of genetic variants as instrumental variables for studying the effects of pharmacological agents. The paradigm can be used to inform on all aspects of drug development and has become increasingly popular over the last decade, particularly given the time- and cost-efficiency with which it can be performed even before commencing clinical studies.

Main body: In this review, we describe the recent emergence of drug target Mendelian randomization, its common pitfalls, how best to address them, as well as potential future directions. Throughout, we offer advice based on our experiences on how to approach these types of studies, which we hope will be useful for both practitioners and those translating the findings from such work.

Conclusions: Drug target Mendelian randomization is nuanced and requires a combination of biological, statistical, genetic, epidemiological, clinical, and pharmaceutical expertise to be utilized to its full potential. Unfortunately, these skillsets are relatively infrequently combined in any given study.

Keywords: Drug development; Drug target; Mendelian randomization; Pharmacology.

Common pitfalls in drug target Mendelian randomization and how to avoid them

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