Spinal pain problems increase with age, but already 21% of Finnish young adults suffer from a musculoskeletal disorder. Chronic widespread pain (CWP) significantly increases one's disability level and up to 50% of people experiencing chronic pain report symptoms of depression. Diagnosing pain is challenging, as it is a subjective feeling and current clinical pain descriptors are not accurate enough to determine pain perception. In this study, variation in the human plasma proteome was investigated with untargeted Mass Spectrometry in young adult twins with weekly chronic multisite spinal pain (n=94), twins with weekly chronic local neck pain (n=99), and healthy twin individuals (n=236). The association of depression with pain and sex-specific proteins in the studied associations was also investigated. The main data analysis approach included multiple regressions which were done with Generalized Linear Mixed Models (GLMM). Of the 411 studied proteins, Aldolase B and Angiotensinogen were negatively associated with weekly chronic concomitant neck and back pain in men. These proteins are known to relate to muscle atrophy and might thus contribute to the development of musculoskeletal pain. In addition, individuals with weekly chronic concomitant neck and back pain had more symptoms of depression than individuals with weekly chronic local neck pain. Further research is needed to identify the key proteins for clinical settings and upcoming pain proteomics research should include both women and men to examine sex differences.

The authors have declared no competing interest.

This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 874724. Equal-Life is part of the European Human Exposome Network. Phenotype and omics data collection in FinnTwin12 cohort has been supported by FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to RJ Rose; AA15416 and K02AA018755 to DM Dick; R01AA015416 to Jessica Salvatore) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248 to JK, and the Centre of Excellence in Complex Disease Genetics (grants 312073, 336823, and 352792 to J Kaprio). J Kaprio acknowledges support from the Academy of Finland (grants 265240, 263278) and the Sigrid Juselius Foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All the twins provided written informed consent before the start of the study. Ethical approval for data collection was obtained from the ethical committee of the Helsinki and Uusimaa University Hospital District and Indiana University's Institutional Review Board.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data used in the analysis is deposited in the Biobank of the Finnish Institute for Health and Welfare (https://thl.fi/en/web/thl-biobank/forresearchers). It is available to researchers after written application and following the relevant Finnish legislation. To ensure the protection of privacy and compliance with national data protection legislation, a data use/transfer agreement is needed, the content and specific clauses of which will depend on the nature of the requested data.