Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Abstract

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (https://www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

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Fig. 1: Study design of this phenome-wide MR study of the plasma proteome.
Fig. 2: A demonstration of PWCoCo analysis.
Fig. 3: Miami plot for the cis-only analysis, with circles representing the MR results for proteins on human phenotypes.
Fig. 4: Regional association plots of IL23R plasma protein level and Crohn’s disease in the IL23R region.
Fig. 5: Enrichment of phenome-wide MR of the plasma proteome with the druggable genome.

Data availability

The data (GWAS summary statistics) used in the analyses described here are freely accessible in the MR-Base platform (https://www.mrbase.org/). All our analysis results for 989 proteins against 225 human phenotypes are freely available to browse, query and download in EpiGraphDB (https://www.epigraphdb.org/pqtl/). An application programming interface and R package documented on the website enable users to programmatically access data from the database.

Code availability

The code used in the MR and colocalization analyses described here are freely accessible via our GitHub repository (https://github.com/MRCIEU/epigraphdb-pqtl/). The MR analysis was conducted using TwoSampleMR R package (https://github.com/MRCIEU/TwoSampleMR/). We implemented the colocalization analysis using the coloc R package (created by C. Wallace and colleagues), which can be downloaded at https://cran.r-project.org/web/packages/coloc/index.html/.

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Acknowledgements

We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them and the whole ALSPAC team, including interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We acknowledge J. Bowden for statistical support and advice relating to MR-Egger regression. This publication is the work of the authors, and J. Zheng will serve as guarantor for the contents of this paper. J.Z. is funded by a Vice-Chancellor’s Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1 and MC_UU_00011/4), GlaxoSmithKline, Biogen and the Cancer Research Integrative Cancer Epidemiology Programme (C18281/A19169). The UK Medical Research Council and Wellcome (grant no. 102215/2/13/2) and the University of Bristol provided core support for ALSPAC. A comprehensive list of grant funding is available on the ALSPAC website (https://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf/). T.R.G. holds a Turing Fellowship with the Alan Turing Institute. G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). M.V.H. is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. This work has been supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol (G.D.S. and T.R.G.). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by the Elizabeth Blackwell Institute for Health Research University of Bristol and the Medical Research Council Proximity to Discovery award. P.E. is supported by Cancer Research UK (CRUK; C18281/A19169). S.L. is funded by the Bau Tsu Zung Bau Kwan Yeun Hing Research and Clinical Fellowship (200008682.920006.20006.400.01) from the University of Hong Kong. J.D. is funded by a NIHR Senior Investigator award. J.D. sits on the International Cardiovascular and Metabolic advisory board for Novartis (since 2010), the UK Biobank Steering Committee (since 2011), and is a member of the MRC International Advisory Group (ING) London (since 2013), the MRC High Throughput Science ‘Omics Panel’, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the AstraZeneca Genomics advisory board (since 2018). P.C.H. is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138.

Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (https://ww.nhsbt.nhs.uk/), which has supported fieldwork and other elements of the trial. DNA extraction and genotyping was co-funded by the NIHR, the NIHR BioResource (https://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. The academic coordinating centre for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014–10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. A complete list of the investigators and contributors to the INTERVAL trial is provided in Di Angelantonio et al.59. The academic coordinating centre thank blood donor center staff and blood donors for participating in the INTERVAL trial.

We gratefully acknowledge all studies and databases that have made their GWAS summary data available for this study: arcOGEN (Arthritis Research UK Osteoarthritis Genetics), BCAC (the Breast Cancer Association Consortium), C4D (Coronary Artery Disease Genetics Consortium), CARDIoGRAM (Coronary ARtery DIsease Genome-wide Replication and Meta-analysis), CKDGen (Chronic Kidney Disease Genetics consortium), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), EAGLE (EArly Genetics and Lifecourse Epidemiology Consortium), EAGLE Eczema (EArly Genetics and Lifecourse Epidemiology Eczema Consortium), EGG (Early Growth Genetics Consortium), ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis), GCAN (Genetic Consortium for Anorexia Nervosa), GEFOS (GEnetic Factors for OSteoporosis Consortium), GIANT (Genetic Investigation of ANthropometric Traits), GIS (Genetics of Iron Status consortium), GLGC (Global Lipids Genetics Consortium), GliomaScan (cohort-based GWAS of glioma), GPC (Genetics of Personality Consortium), GUGC (Global Urate and Gout consortium), HaemGen (hematological and platelet traits genetics consortium), IGAP (International Genomics of Alzheimer’s Project), IIBDGC (International Inflammatory Bowel Disease Genetics Consortium), ILCCO (International Lung Cancer Consortium), IMSGC (International Multiple Sclerosis Genetic Consortium), ISGC (International Stroke Genetics Consortium), MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium), MDACC (MD Anderson Cancer Center), MESA (Multi-Ethnic Study of Atherosclerosis), Neale’s lab (a team of researchers from Benjamin Neale’s group, who made the UK Biobank GWAS summary statistics publically available), OCAC (Ovarian Cancer Association Consortium), IPSCSG (the International PSC study group), NHGRI-EBI GWAS catalog (National Human Genome Research Institute and European Bioinformatics Institute Catalog of published GWAS), PanScan (Pancreatic Cancer Cohort Consortium), PGC (Psychiatric Genomics Consortium), Project MinE consortium, ReproGen (Reproductive ageing Genetics consortium), SSGAC (Social Science Genetics Association Consortium), TAG (Tobacco and Genetics Consortium) and the UK Biobank.

J.Z. acknowledges his grandmother ChenZhu for all her support, may she rest in peace.

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Contributions

J.Z., V.H. and D.B. performed the MR analysis. J.Z. and D.B. performed the colocalization analysis. J.Z. performed the conditional analysis. V.H., Y.L., B.E. and T.R.G. developed the database and web browser. J.Z., V.W. and M.R.H. performed the drug target prioritization and enrichment analysis. J.Z. and R.S. conducted the druggable genome analysis. J.Z. and P.E. conducted the pathway and protein–protein interaction analysis. M.R.H., A.G., T.G.R., B.E., H.M.M., J.Y., C.L., S.L. and J.R. conducted supporting analyses. J.R.S., B.B.S., J.D., H.R. and J.C.M. provided key data and supported the MR analysis. M.R.H., S.B., J.Z.L., K.E., L.M., M.V.H., D.W. and M.R.N. reviewed the paper and provided key comments. J.Z., V.H., D.B., V.W., P.C.H., A.S.B., G.D.S., G.H., R.A.S. and T.R.G. are the members of the Proteome MR writing group and wrote the manuscript. J.Z., T.R.G. and R.A.S. conceived and designed the study and oversaw all analyses.

Corresponding authors

Correspondence to Jie Zheng or Robert A. Scott or Tom R. Gaunt.

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Competing interests

A.G., L.M., M.R.H., D.W., M.R.N., R.S. and R.A.S. are employees and shareholders in GlaxoSmithKline. H.R., J.Z.L. and K.E. are employees and shareholders in Biogen. J.Z. and V.H. are employed on a grant funded by GlaxoSmithKline. D.B. is employed on a grant funded by Biogen. T.R.G., G.H. and G.D.S. receive funding from GlaxoSmithKline and Biogen for the work described here. A.S.B. has received grants from Merck, Novartis, Biogen, Pfizer and AstraZeneca. M.V.H. 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. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), the British Heart Foundation and the Wellcome Trust.

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Supplementary Figs. 1–10 and Supplementary Note

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Supplementary Tables 1–27

Supplementary Data 1

Data for bidirectional MR and Steiger filtering results.

Supplementary Data 2

Data for a detailed comparison within each protein group using Venn diagrams.

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Zheng, J., Haberland, V., Baird, D. et al. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases. Nat Genet (2020). https://doi.org/10.1038/s41588-020-0682-6

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