• Amy Elise Martinsen, Sigrid Børte, Mari Spildrejorde, Ben Michael Brumpton, Ingrid Heuch, John-Anker Zwart, and Bendik Slagsvold Winsvold.
• Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
• Spine. 2025 Jan 3.

Study DesignGenome-wide association study (GWAS) meta-analysis with downstream analyses.ObjectiveTo explore the genetic architecture of chronic low back pain (cLBP) and identify underlying biological mechanisms that contribute to its development.Summary Of Background DataChronic low back pain is prevalent and debilitating, with many cases having no identifiable biological cause. Current treatment options provide only limited relief, highlighting the need for a deeper understanding of the genetic and molecular factors involved in cLBP pathogenesis. Identifying these factors may lead to more effective, targeted therapies.MethodsWe conducted a GWAS meta-analysis involving 325,078 participants from the UK Biobank and the HUNT population studies. This was followed by downstream analyses, including gene prioritization, tissue enrichment analysis, and functional gene set analysis. Genetic loci were examined for their association with cLBP, and gene sets were assessed for functional relevance.ResultsEighteen genetic loci associated with cLBP were identified corresponding to as many prioritized genes, including eight novel genes not previously linked to the condition. Tissue enrichment analysis highlighted significant involvement of hippocampal brain tissue, suggesting central memory processes may contribute to cLBP. Functional gene set analysis identified 37 gene sets, many related to transcription factors involved in bone and cartilage maintenance. Literature on the prioritized genes suggested a potential role for neurological, cartilaginous, and inflammatory mechanisms, including genes implicated in the innervation of intervertebral discs, inflammatory cell death, and central sensitization. Comparison with previous GWASs indicated potential differences between individuals who seek medical care and those who do not.ConclusionThis study enhances our understanding of the genetic basis of cLBP, revealing distinct biological mechanisms and suggesting the existence of patient subgroups with differing treatment needs. These insights may pave the way for more tailored and effective treatment approaches in the future.Level Of EvidenceLevel 3 (observational study).Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.

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