Abstract
Chronic musculoskeletal pain affects all aspects of human life. However, mechanisms of its genetic control remain poorly understood. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. Here, we apply principal component analysis to reduce phenotype heterogeneity of chronic musculoskeletal pain at four locations: the back, neck/shoulder, hip, and knee. Using matrices of genetic covariances, we constructed four genetically independent phenotypes (GIPs) with the leading GIP (GIP1) explaining 78.4% of the genetic variance of the analyzed conditions, and GIP2–4 explain progressively less. We identified and replicated five GIP1-associated loci and one GIP2-associated locus and prioritized the most likely causal genes. For GIP1, we showed enrichment with multiple nervous system-related terms and genetic correlations with anthropometric, sociodemographic, psychiatric/personality traits and osteoarthritis. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and reflecting pain perception and processing.
Highlights
Evidence from recent studies indicates that pain at different anatomical sites shares a common genetic component[24,25,26]. This suggests that combining several pain phenotypes in a single analytical framework may facilitate the discovery of common genetic factors – chronic musculoskeletal pain genes and pathways
The genetically independent phenotypes (GIPs) are defined as a weighted sum of the original phenotypes, with weights selected in such a way that the first GIP (GIP1) explains most genetic variance of and covariance between the studied traits, with the later GIPs (GIP2–4) explaining progressively less
The four weights defining GIP1 based on the four chronic pain traits turned out to be approximately the same (Fig. 2a, Supplementary Fig. 1)
Summary
DEPICT gene set and tissue/cell type enrichment analyses provided statistically significant results only for GIP1 (Supplementary Data 8c–f). For SNP sets associated with GIP1 with P < 5e-08, tissue/cell type enrichment with FDR < 0.05 was found for two terms: the “Neural Stem Cells” cell type and “Retina” tissue. Relaxing the significance threshold of input SNPs to P < 1e-05 led to identification of 24 additional tissues, all of which were related to CNS. The same pattern was observed for gene set enrichment (for SNPs with P < 1e-05), revealing 462 terms mainly involved in nervous system function, development and morphology “regulation of nervous system development”, “axonogenesis”, “synapse”, and “regulation of transmission of nerve impulse”) The same pattern was observed for gene set enrichment (for SNPs with P < 1e-05), revealing 462 terms mainly involved in nervous system function, development and morphology (e.g. “regulation of nervous system development”, “axonogenesis”, “synapse”, and “regulation of transmission of nerve impulse”)
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