Dai Zhisen, Wu Yanlin, Huang Huaqing, Zheng Huizhe
Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
Pain Research Institute of Fujian Medical University, Fuzhou, Fujian, China.
Sci Rep. 2025 Jul 1;15(1):21999. doi: 10.1038/s41598-025-04379-5.
Chronic widespread musculoskeletal pain (CWP), a core symptom of fibromyalgia, is a complex condition with an unclear pathogenesis. Despite findings from genome-wide association studies (GWAS), translating genetic risk variants into therapeutic targets remains challenging due to limited understanding of their functional roles in CWP. In this study, we developed an integrative analytical pipeline to efficiently link genetic associations with novel risk genes for CWP. By combining high-throughput data from multiple sources, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), summary-based Mendelian randomization (SMR), and Bayesian co-localization analyses. This approach allowed us to prioritize genes that may increase the risk of CWP by altering protein abundance and gene expression in the brain. We further examined these genes using various advanced methodologies to validate their significance. We identified eight genes expressed in the brain, whose protein levels were associated with CWP. Four of these genes were confirmed through a subsequent PWAS, while three showed associations with cis-regulated mRNA expression. Only four genes, GMPPB, COMT, NME1, and GPX1, passed SMR and Bayesian colocalization analyses. These genes were expressed in pain-related brain regions and showed selective expression in oligodendrocytes, microglia, dopaminergic neurons, and interneurons. Additionally, COMT and NME1 were identified as potential druggable targets using the DGIdb and DrugBank databases. Our findings suggest that GMPPB, COMT, NME1, and GPX1 are potential risk genes for CWP, offering new insights into the molecular mechanisms underlying the condition. These genes represent promising targets for future research and therapeutic intervention development.
慢性广泛性肌肉骨骼疼痛（CWP）是纤维肌痛的核心症状，是一种发病机制不明的复杂病症。尽管全基因组关联研究（GWAS）取得了一些发现，但由于对其在CWP中的功能作用了解有限，将遗传风险变异转化为治疗靶点仍然具有挑战性。在本研究中，我们开发了一种综合分析流程，以有效地将遗传关联与CWP的新风险基因联系起来。通过整合来自多个来源的高通量数据，我们结合了蛋白质组全关联研究（PWAS）、转录组全关联研究（TWAS）、基于汇总数据的孟德尔随机化（SMR）和贝叶斯共定位分析。这种方法使我们能够对可能通过改变大脑中的蛋白质丰度和基因表达而增加CWP风险的基因进行优先级排序。我们使用各种先进方法进一步研究这些基因，以验证它们的重要性。我们鉴定出八个在大脑中表达的基因，其蛋白质水平与CWP相关。其中四个基因通过后续的PWAS得到证实，而三个基因显示出与顺式调控的mRNA表达相关。只有四个基因，即GMPPB、COMT、NME1和GPX1，通过了SMR和贝叶斯共定位分析。这些基因在与疼痛相关的脑区表达，并在少突胶质细胞、小胶质细胞、多巴胺能神经元和中间神经元中表现出选择性表达。此外，使用DGIdb和DrugBank数据库将COMT和NME1鉴定为潜在的可药物靶向。我们的研究结果表明，GMPPB、COMT、NME1和GPX1是CWP的潜在风险基因，为该病症的分子机制提供了新的见解。这些基因代表了未来研究和治疗干预开发的有希望的靶点。
