Abstract

Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10−6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases.

Inflammation is associated with a variety of diseases. Here, the authors identify 266 genetic loci associated with C-reactive protein levels, a marker of inflammation, in >500,000 Europeans, along with associated pathways, clinical outcomes and potential causal associations with disease.

Details

Title
Genetic analysis of over half a million people characterises C-reactive protein loci
Author
Said, Saredo 1 ; Pazoki, Raha 2   VIAFID ORCID Logo  ; Karhunen, Ville 3 ; Võsa, Urmo 4   VIAFID ORCID Logo  ; Ligthart, Symen 5 ; Bodinier, Barbara 1   VIAFID ORCID Logo  ; Koskeridis, Fotios 6   VIAFID ORCID Logo  ; Welsh, Paul 7 ; Alizadeh, Behrooz Z. 8 ; Chasman, Daniel I. 9 ; Sattar, Naveed 7   VIAFID ORCID Logo  ; Chadeau-Hyam, Marc 10   VIAFID ORCID Logo  ; Evangelou, Evangelos 11   VIAFID ORCID Logo  ; Jarvelin, Marjo-Riitta 12   VIAFID ORCID Logo  ; Elliott, Paul 13   VIAFID ORCID Logo  ; Tzoulaki, Ioanna 14   VIAFID ORCID Logo  ; Dehghan, Abbas 15   VIAFID ORCID Logo 

1  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
2  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Brunel University London, Cardiovascular and Metabolic Research Group, Department of Life Sciences, London, UK (GRID:grid.7728.a) (ISNI:0000 0001 0724 6933); Brunel University London, The Centre for Inflammation Research and Translational Medicine (CIRTM), London, UK (GRID:grid.7728.a) (ISNI:0000 0001 0724 6933); Brunel University London, Centre for Health and Well-being Across the Life Course, London, UK (GRID:grid.7728.a) (ISNI:0000 0001 0724 6933) 
3  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); University of Oulu, Centre for Life Course Health Research, Oulu, Finland (GRID:grid.10858.34) (ISNI:0000 0001 0941 4873); University of Oulu, Research Unit of Mathematical Sciences, Oulu, Finland (GRID:grid.10858.34) (ISNI:0000 0001 0941 4873) 
4  Institute of Genomics, University of Tartu, Estonian Genome Centre, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
5  University Hospital Antwerp, Department of Intensive Care, Antwerp, Belgium (GRID:grid.411414.5) (ISNI:0000 0004 0626 3418) 
6  University of Ioannina Medical School, Department of Hygiene and Epidemiology, Ioannina, Greece (GRID:grid.9594.1) (ISNI:0000 0001 2108 7481) 
7  University of Glasgow, Institute of Cardiovascular and Medical Sciences, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X) 
8  University of Groningen and University Medical Centre Groningen, Department of Epidemiology, Groningen, the Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
9  Brigham & Women’s Hospital, Division of Preventive Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Brigham and Women’s Hospital, Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
10  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Imperial College London, MRC-PHE Centre for Environment and Health, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
11  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); University of Ioannina Medical School, Department of Hygiene and Epidemiology, Ioannina, Greece (GRID:grid.9594.1) (ISNI:0000 0001 2108 7481) 
12  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); University of Oulu, Centre for Life Course Health Research, Oulu, Finland (GRID:grid.10858.34) (ISNI:0000 0001 0941 4873) 
13  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Imperial College London, MRC-PHE Centre for Environment and Health, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); UK Dementia Research Institute at Imperial College London, Burlington Danes Building, Hammersmith Hospital, London, UK (GRID:grid.413629.b) (ISNI:0000 0001 0705 4923); National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
14  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); University of Ioannina Medical School, Department of Hygiene and Epidemiology, Ioannina, Greece (GRID:grid.9594.1) (ISNI:0000 0001 2108 7481); Imperial College London, MRC-PHE Centre for Environment and Health, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); UK Dementia Research Institute at Imperial College London, Burlington Danes Building, Hammersmith Hospital, London, UK (GRID:grid.413629.b) (ISNI:0000 0001 0705 4923) 
15  Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Imperial College London, MRC-PHE Centre for Environment and Health, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); UK Dementia Research Institute at Imperial College London, Burlington Danes Building, Hammersmith Hospital, London, UK (GRID:grid.413629.b) (ISNI:0000 0001 0705 4923) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-29650-5
ProQuest document ID
2653413547
Copyright
© The Author(s) 2022. corrected publication 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.