Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

Lingyan Chen; James E Peters; Bram Prins; Elodie Persyn; Matthew Traylor; Praveen Surendran; Savita Karthikeyan; Ekaterina Yonova-Doing; Emanuele Di Angelantonio; David J Roberts; Nicholas A Watkins; Willem H Ouwehand; John Danesh; Cathryn M Lewis; Paola G Bronson; Hugh S Markus; Stephen Burgess; Adam S Butterworth; Joanna M M Howson

doi:10.1038/s41467-022-33675-1

Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

Nat Commun. 2022 Oct 17;13(1):6143. doi: 10.1038/s41467-022-33675-1.

Authors

Lingyan Chen^{1

2}, James E Peters^{1

3}, Bram Prins¹, Elodie Persyn^{1

4

5}, Matthew Traylor^{2

6}, Praveen Surendran^{1

7}, Savita Karthikeyan¹, Ekaterina Yonova-Doing^{1

2}, Emanuele Di Angelantonio^{1

8

9

10

11}, David J Roberts^{9

12

13}, Nicholas A Watkins¹⁴, Willem H Ouwehand^{8

14

15

16}, John Danesh^{1

8

9

10

17}, Cathryn M Lewis^{4

18}, Paola G Bronson¹⁹, Hugh S Markus²⁰, Stephen Burgess^{1

8

21}, Adam S Butterworth^{1

8

9

10}, Joanna M M Howson^{22

23}

Affiliations

¹ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK.
³ Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
⁴ Department of Medical and Molecular Genetics, King's College London, London, UK.
⁵ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁷ Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, Cambridge, UK.
⁸ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
⁹ National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
¹⁰ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹¹ Health Data Science Research Centre, Human Technopole, Milan, Italy.
¹² NHS Blood and Transplant-Oxford Centre, Level 2, John Radcliffe Hospital, Oxford, UK.
¹³ Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
¹⁴ NHS Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, UK.
¹⁵ Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁶ Wellcome Sanger Institute, Hinxton, UK.
¹⁷ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
¹⁸ Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
¹⁹ R&D Translational Biology, Biogen, Inc., Cambridge, MA, USA.
²⁰ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
²¹ Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
²² British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [email protected].
²³ Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK. [email protected].

Abstract

Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10^-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Atrial Fibrillation* / genetics
Blood Proteins / genetics
Diabetes Mellitus, Type 2* / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Proteome / genetics
Risk Factors
Stroke* / genetics

Substances

Blood Proteins
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding