Mendelian Randomization Analysis Identifies Causal Effects of Multi-Site Chronic Pain on Obstructive Sleep Apnea

Zuxing Wang,1,* Lili Chen,1,* Ruishi Kang,2,* Zhuowei Li,2 Jiangang Fan,2 Yi Peng,3,* Yunqi He,4,5 Xiaolong Zhao2 1Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, 610072, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Department of Otorhinolaryngology Head and Neck Surgery, Second People’s Hospital of Chengdu, Chengdu, 610000, People’s Republic of China; 4Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 5Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaolong Zhao, Email [email protected] Yunqi He, Email [email protected]: Observational studies have suggested an association between obstructive sleep apnea (OSA) and chronic pain disorders, but causal evidence have not been confirmed.Methods: Here we performed Mendelian randomization (MR) study to explore the potential causal association and mediating roles of modifiable factors between multi-site chronic pain (MCP) and OSA. Independent single nucleotide polymorphisms (SNPs) (N=26) from MCP GWAS (n=387,649) in the UK Biobank were used as instrumental variables to test associations with OSA from the FinnGen consortium, which encompassed 16,761 individuals with OSA cases and 201,194 individuals without OSA.Results: MR analyses provide genetic evidence to predict MCP on the risk of OSA. Specifically, a per-site increase in multi-site chronic pain was linked to a 184% higher risk of OSA (ORIVW = 1.84, 95% CI = 1.29– 2.63, p = 7.24× 10− 4). However, we also performed reverse association analyses and found no significant casual effect of OSA on MCP. MR estimates were in agreement regardless of the method used, such as MR-egger, weighted median and weighted mode, thereby demonstrating the accuracy of the causal associations. Through mediation analyses, we found that body mass index (BMI), waist circumference, and educational attainment explained a substantial proportion of the association between MCP and OSA (proportion mediated=21.13%; 26.57% and 9.66% respectively).Conclusion: Our findings suggest that both pain management interventions, prevention of obesity and health education are likely to be effective strategies to reduce OSA risk in individuals with MCP.Keywords: Mendelian randomization, multi-site chronic pain, obstructive sleep apnea, causal effect, mediation effect