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PLoS Genet. 2018 Sep 27;14(9):e1007601. doi: 10.1371/journal.pgen.1007601. eCollection 2018 Sep.

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Author information

1
Seattle Epidemiologic Research and Information Center (ERIC), Department of Veterans Affairs Office of Research and Development, Seattle, Washington, United States of America.
2
Division of Rehabilitation Care Services, VA Puget Sound Health Care System, Seattle, Washington, United States of America.
3
Department of Rehabilitation Medicine, University of Washington, Seattle, Washington, United States of America.
4
Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
5
Polyomica, 's-Hertogenbosch, the Netherlands.
6
Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, Russia.
7
Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics SD RAS, Novosibirsk, Russia.
8
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
9
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
10
Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, United States of America.
11
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
12
California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
13
Department of Public Health, University of Split Medical School, Split, Croatia.
14
Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, United States of America.
15
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
16
Department of Medicine, University of Göteborg, Göteborg, Sweden.
17
Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
18
Clinical Epidemiology Unit, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
19
Centre for Genomic and Experimental Medicine, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
20
Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Sweden.
21
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Göteborg, Sweden.
22
Department of Orthopedics and Rehabilitation, Oregon Health and Science University, Portland, Oregon, United States of America.
23
Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.
24
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, United States of America.
25
Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, California, United States of America.
26
Genos Ltd, Osijek, Croatia.
27
Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.
28
Department of Health Services, University of Washington, Seattle, Washington, United States of America.
29
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
30
Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, United States of America.
31
Department of Orthopedics, Skane University Hospital, Lund University, Malmö, Sweden.
32
Departments of Medicine and Rheumatology, University of California Davis, Sacramento, California, United States of America.
33
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
34
Hospital "Sveti Ivan", Zagreb, Croatia.
35
Departments of Medicine and Epidemiology, University of Maryland, Baltimore, Maryland, United States of America.
36
Department of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
37
School of Public Health, Oregon Health and Science University, Portland, Oregon, United States of America.
38
Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
39
Division of Population Health Sciences, School of Medicine, University of Dundee, Dundee, United Kingdom.
40
MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, United Kingdom.

Abstract

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

PMID:
30261039
DOI:
10.1371/journal.pgen.1007601
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Conflict of interest statement

BMP serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; YSA and LK are founders and co-owners of PolyOmica, a private genomics research organization; these relationships do not pose known conflicts with the content of this work presented. We the authors do not have any other financial interests that could create a potential conflict or the appearance of a potential conflict of interest with regard to this work.

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