Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

Huiling Zhao; Humaria Rasheed; Therese Haugdahl Nøst; Yoonsu Cho; Yi Liu; Laxmi Bhatta; Arjun Bhattacharya; Global Biobank Meta-analysis Initiative; Gibran Hemani; George Davey Smith; Ben Michael Brumpton; Wei Zhou; Benjamin M Neale; Tom R Gaunt; Jie Zheng

doi:10.1016/j.xgen.2022.100195

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

Cell Genom. 2022 Nov 9;2(11):None. doi: 10.1016/j.xgen.2022.100195.

Authors

Huiling Zhao¹, Humaria Rasheed^{1

2

3}, Therese Haugdahl Nøst^{2

4}, Yoonsu Cho¹, Yi Liu¹, Laxmi Bhatta², Arjun Bhattacharya^{5

6}; Global Biobank Meta-analysis Initiative; Gibran Hemani¹, George Davey Smith^{1

7}, Ben Michael Brumpton^{3

8

9}, Wei Zhou^{10

11

12}, Benjamin M Neale^{11

12}, Tom R Gaunt^{1

7}, Jie Zheng^{1

13

14}

Affiliations

¹ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
² K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
³ Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway.
⁴ Department of Community Medicine, UIT The Arctic University of Norway, 9037 Tromsø, Norway.
⁵ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁶ Institute of Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁷ NIHR Bristol Biomedical Research Centre, Bristol, UK.
⁸ HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, 7600 Levanger, Norway.
⁹ Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹⁰ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹² Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹³ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁴ Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence in both ancestries and seven pairs with specific effects in the two ancestries separately. Integrating these MR signals with clinical trial evidence, we prioritized 16 pairs for investigation in future drug trials. Our results highlight the value of proteome-wide MR in informing the generalizability of drug targets for disease prevention across ancestries and illustrate the value of meta-analysis of biobanks in drug development.

Keywords: complex diseases; drug target prioritization; multi-ancestry Mendelian randomization; plasma proteome.

Abstract

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