Chronic back pain is the number one cause of years lived with disability worldwide. In a new study, Pradeep Suri of the Department of Veterans Affairs in Seattle, Washington, and colleagues in the United States and Europe, in association with Dr. Frances Williams from King's College London's Department of Twin Research and Genetic Epidemiology, identified three novel genetic variants associated with chronic back pain. The study, which was published in the open-access journal PLOS Genetics, links the risk for back pain with variants in genes controlling skeletal development, among other pathways. These findings may help to elucidate the basic biology underlying this common symptom, and point toward avenues for the eventual development of new therapies.
The researchers conducted a genome-wide association study in 158,000 adults of European ancestry, including over 29,000 individuals with chronic back pain, looking for gene variants that were associated with the presence of back pain. The strongest association was with a variant in the SOX5 gene, which is a transcription factor involved in virtually all phases of embryonic development. Inactivation of SOX5 has previously been linked to defects in cartilage and skeleton formation in mice, supporting the hypothesis that the variant discovered in this study may contribute to chronic back pain through its influence on some aspect of skeletal development. The association of the SOX5 variant with chronic back pain was replicated in another group of over 280,000 individuals, including over 50,000 individuals with chronic back pain. A second gene, previously associated with intervertebral disc herniation, was also linked to back pain, as was a third gene that plays a role in spinal cord development, possibly implicating pain sensation or mood in the risk for back pain.
"The results of our genome-wide association study point to multiple pathways that may influence risk for chronic back pain," said Suri. "Chronic back pain is linked to changes in mood, and the role of the central nervous system in the transition from acute to chronic back pain is well-recognized. However, the top two genetic variants we identified suggest causes implicating the peripheral structures, such as the spine. We expect that further large-scale genetic studies will reveal the importance of both peripheral and central contributors to the complex experience of chronic back pain."
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Citation: Suri P, Palmer MR, Tsepilov YA, Freidin MB, Boer CG, Yau MS, et al. (2018) Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. PLoS Genet 14(9): e1007601. https:/
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Funding: Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grants R01HL105756. This study was supported by the European Commissions' Seventh Framework Programme funded project PainOmics (Grant agreement n. 602736) Dr. Suri was supported by VA Career Development Award # 1IK2RX001515 from the United States (U.S.) Department of Veterans Affairs Rehabilitation Research and Development (RR&D) Service. Dr. Suri is a Staff Physician at the VA Puget Sound Health Care System. The contents of this work do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL085251, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham Heart Study: From the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278), and by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging, (AG08122, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Framingham Heart Study or Boston University School of Medicine. Generation Scotland: Generation Scotland (GS) received core funding from the Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL) Reference 104036/Z/14/Z). Johnston County Osteoarthritis Project: The JoCo is supported in part by S043, S1734, & S3486 from the CDC/Association of Schools of Public Health; 5-P60-AR30701 & 5-P60-AR49465-03 from NIAMS/NIH; genotyping was supported by Algynomics, Inc. Mr. Os Sweden: MrOS Sweden is supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Knut and Alice Wallenberg Foundation, the Torsten Soderberg Foundation, and the Novo Nordisk Foundation, the ALF/FoUU research grant in Skane, Herman Järnhardts, Kocks and Österluds Foundations. Osteoporotic Fractures in Men (Mr Os) US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, U01 AG042140, U01 AG042143, U01 AG042124, U01 AG042145, U01 AG042139, U01 AG042168, U01 AR066160, UL1 TR000128, and UL1 RR024140. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973. Osteoarthritis Initiative (OAI): This study was supported by the American Recovery and Reinvestment Act (ARRA) through grant number RC2-AR-058950 from NIAMS/NIH. The OAI is public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the NIH. Additional support was provided by NIH grant P30-DK072488. Rotterdam Study: The Rotterdam Study is supported by the Erasmus 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 Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. Study of Osteoporotic Fractures: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973. 10,001 Dalmatians: Support for field work from University of Split and Zagreb Medical Schools, the Institute for Antropological Research in Zagreb and the Croatian Institute for Public Health. The SNP genotyping for the Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. The SNP genotyping for the Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. The SNP genotyping was performed by AROS Applied Biotechnology, Aarhus, Denmark. The study was funded by the Medical Research Council UK, The Croatian Ministry of Science, Education and Sports (grant 216-1080315-0302), the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947), the Croatian Science Foundation (grant 8875), the Centre for Research Excellence in Personalized Medicine and the Centre of Competencies for Integrative Treatment, Prevention and Rehabilitation using TMS. TwinsUK: TwinsUK receives funding from the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013 to Twins UK); the National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. UK Biobank: This research has been conducted using the UK Biobank Resource (project # 18219). We are grateful to the UK Biobank participants for making such research possible. Dr. Smith is a Research Scientist at the VA Puget Sound Health Care System. The work of Dr. Tsepilov was partly supported by the Russian Ministry of Science and Education under the 5-100 Excellence Programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: B.M.P. 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; Y.S.A. and L.K. 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.