Bidirectional Two-Sample Mendelian Randomization Analysis Reveals Causal Associations Between Modifiable Risk Factors and Fibromyalgia

Wei Zu,1,* Shaojiong Zhou,2,* Tao Du,1 Chenyanwen Zhu,3 Siyue Nie,4 Hongwei Zhu1 1Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology & Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, People’s Republic of China; 3 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 4Chinese PLA Medical School; Department of Oncology, Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongwei Zhu, Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China, Email zhuhongwei@xwh.ccmu.edu.cnIntroduction: This study aims to investigate the potential causal effects of modifiable risk factors on Fibromyalgia (FM).Methods: Genetic variants associated with 34 exposure factors were obtained from Genome-wide association studies (GWAS). Summary statistics for FM were acquired from the FinnGen consortium. Bidirectional Mendelian randomization (MR) analysis was conducted between all exposures and outcomes. The inverse-variance weighted (IVW) method was employed as the primary estimation technique. Heterogeneity and pleiotropy were assessed using MR-PRESSO global test, the weighted median, Cochran’s Q statistic and MR-Egger.Results: Depression (OR=2.087, 95% CI: 1.466– 2.971), alcohol consumption (OR=1.489, 95% CI: 1.094– 2.028), body fat percentage (OR=1.524, 95% CI: 1.153– 2.013) and body mass index (BMI) (OR=1.542, 95% CI: 1.271– 1.872) were associated with an increased risk of FM among genetically susceptible individuals. Conversely, higher education level (OR=0.404, 95% CI: 0.297– 0.549), longer years of education (OR=0.489, 95% CI: 0.290– 0.825) and higher household income (OR=0.328, 95% CI: 0.215– 0.502) were protective against FM. Additionally, rheumatoid arthritis (OR=1.138, 95% CI: 1.061– 1.221) and ankylosing spondylitis (OR=1.079, 95% CI: 1.021– 1.140) were identified as important risk factors for FM.Conclusion: This MR study unveiled a complex causal relationship between modifiable risk factors and FM. Psychosocial factors significantly increase the odds of FM, while obesity and some autoimmune diseases that frequently coexist with FM demonstrate causal associations. Additionally, lifestyle habits such as alcohol consumption are causally related to FM. Further investigation is needed to determine whether risk factors contribute to the pathogenesis of FM through mechanisms involving central sensitization, inflammatory, and hyperalgesia. This study enhances our understanding of the factors that drive FM onset and progression, offering valuable insights for future targeted prevention and treatment strategies.Keywords: fibromyalgia, modifiable risk factors, causal association, Mendelian randomization