TY - JOUR

T1 - Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain

AU - Rahman, Md Shafiqur

AU - Winsvold, Bendik S.

AU - Chavez Chavez, Sergio O.

AU - Børte, Sigrid

AU - Tsepilov, Yakov A.

AU - Sharapov, Sodbo Zh

AU - Aulchenko, Yurii S.

AU - Hagen, Knut

AU - Fors, Egil A.

AU - Hveem, Kristian

AU - Zwart, John Anker

AU - Van Meurs, Joyce B.

AU - Freidin, Maxim B.

AU - Williams, Frances M.K.

N1 - Funding Information: Funding MSR received funding from the European Union’s Horizon 2020 research and innovation program IMforFUTURE, under H2020-MSCA-ITN grant agreement number 721815. The work of YAT was supported by PolyOmica and by the Russian Foundation for Basic Research (project 19-015-00151). The work of SZS was supported by the Russian Ministry of Science and Education under the 5-100 Excellence Programme and by the Ministry of Education and Science of the RF via the Institute of Cytology and Genetics SB RAS (project number 0259-2021-0009/ AAAA-A17-117092070032-4). The work of YSA was supported by PolyOmica. Funding Information: 11Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway 12Clinical Research Unit Central Norway, St Olavs University Hospital, Trondheim, Norway 13Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway 14HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway Acknowledgements The authors would like to thank all the participants of UK Biobank, The Nord-Trøndelag Health Survey, English Longitudinal Study of Aging, TwinsUK and Rotterdam study I, II and III. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. The UK Biobank study was approved by the National Health Service National Research Ethics Service (ref. 11/NW/0382) and all participants provided written informed consent. Genome-wide association analysis was performed using the UK Biobank resource under project number 18219. The English Longitudinal Study of Ageing is jointly run by University College London, Institute for Fiscal Studies, University of Manchester and National Centre for Social Research. Genetic analyses have been carried out by UCL Genomics and funded by the Economic and Social Research Council and the National Institute on Aging. Data governance was provided by the METADAC data access committee, funded by ESRC, Welcome and MRC (2015-2018: Grant Number MR/N01104X/1 2018-2020: Grant Number ES/S008349/1). TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The genotyping was financed by the National Institute of Health (NIH), University of Michigan, The Norwegian Research Council and Central Norway Regional Health Authority and the Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU). The genotype quality control and imputation has been conducted by the K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU). The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NWO); The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII) and the Municipality of Rotterdam. Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Background and objectives: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. Methods: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. Results: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca2+ transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. Conclusions: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

AB - Background and objectives: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. Methods: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. Results: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca2+ transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. Conclusions: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

KW - epidemiology

KW - fibromyalgia

KW - genetic

KW - polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85105748588&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2020-219624

DO - 10.1136/annrheumdis-2020-219624

M3 - Article

C2 - 33926923

AN - SCOPUS:85105748588

VL - 80

SP - 1227

EP - 1235

JO - Annals of the rheumatic diseases

JF - Annals of the rheumatic diseases

SN - 0003-4967

IS - 9

ER -