Associations Of Sleep Characteristics With Polycystic Ovary Syndrome

Background:Polycystic ovary syndrome(PCOS)is characterized by reproductive endocrinology and metabolic abnormalities,affecting reproductive-aged women.Women with PCOS suffer from multfold clinical symptoms,including psychological comorbidities,reproductive problems and metabolic characteristics.PCOS not only have a significant negative impact on women’s fertility,but result in short-and-long-term complications that negatively impact woman’s physical and mental health.While the pathogenesis and etiology of PCOS are yet unknown,there is a widespread consensus among experts that it may be related to genetics,environment,and emotions.Observational studies have demonstrated that polycystic patients are frequently accompanied by sleep disorders and sleep disturbances,which are more prevalent in patients with a combination of metabolic syndrome.Due to the limitations of observational studies,the causality between sleep characteristics and PCOS as well as its metabolic complications remained unknown.The mendelian randomization(MR)method contributes to the solution of the aforementioned issues.By selecting genetic variants significantly associated with exposure factors as instrumental variables,the MR method,in accordance with the principle of random assignment of alleles during gamete meiosis(Mendel’s second law),overcomes the effects of confounding factors and reverse causal associations in traditional epidemiological studies,and thus inferring causal relationships between two traits.Therefore,we aimed to apply a two-sample bidirectional MR approach,selecting genetic variants significantly associated with sleep characteristics,polycystic ovary syndrome and metabolic syndrome(Met S)as instrumental variables,to reveal the causal effect of sleep on the risk of polycystic ovary syndrome and metabolic syndrome.Methods:To retrieve and extract summary statistics from the public database on genome-wide association studies(GWAS)of sleep characteristics(including sleep duration,sleep chronotype,insomnia,daytime sleepiness,and sleep apnea),PCOS and metabolic syndrome.First,sleep-related parameters were employed as exposure variables,single nucleotide polymorphism(SNP)loci strongly correlated with the aforementioned exposures were chosen as genetic instrumental variables(IV),and PCOS and Met S were used as outcome factors for positive MR analysis.A reverse MR analysis(swapping exposure with outcome components)was carried out in the second step to determine whether PCOS and Met S affect sleep characteristics.Inverse-variance weighted method was supposed as the main analysis method for data analysis,and the odds ratio(OR),95% confidence interval(CI)and P-value were the main effect indicators.With the purpose of checking the reliability of MR results,further pleiotropy,heterogeneity and sensitivity analyses included the MR-Egger regression method、weighted median method、MR-Egger intercept analysis、MR pleiotropy residual sum and outlier test(MR-PRESSO)、Cochran’s Q test and leave-one-out analysis.Results:We divided the two-sample bidirectional MR analysis into two parts.The first part explored the causal effect between sleep and PCOS,and the second part investigated the causal association between sleep and Met S.In the first part,forward MR analysis found an association between sleep duration and the risk of developing PCOS,the MR-IVW results were statistically significant(OR=0.611,95%CI:0.387-0.966,P=0.035);However,no evidence were found that sleep chronotype,insomnia,excessive daytime sleepiness and sleep apnea were linked to the development of PCOS(P>0.05).In a reverse MR analysis,MR-IVW analysis found evidence that having PCOS may alter sleep chronotype(OR=0.968,95%CI:0.952-0.984,P=1.662E-04),but not other sleep characteristics.In the second part,in forward MR analysis,excessive daytime sleepiness(OR=2.002,95%CI:1.122-3.571,P=0.019)and sleep apnea(OR=1.141,95%CI:1.002-1.298,P=0.046)separately promote the development of Met S,while in a reverse MR analysis,MR-IVW found that developing Met S increased the odds of daytime sleepiness(OR=1.012,95%CI:1.007-1.016,P=1.82E-06)and sleep apnea(OR=1.061,95%CI:1.004-1.120,P=0.034).No evidence were found that the other sleep characteristics were linked to the Met S(P>0.05).Conclusions:1.Our MR analysis revealed that genetically predicted sleep duration may play a role in the development of PCOS,but the remaining sleep characteristics are not;Developing PCOS may cause changes in sleep patterns.Therefore,active sleep adjustment may be beneficial in women with PCOS.2.Our MR analyses affirmed a bidirectional causal relationship between sleep apnea and daytime sleepiness and Met S.Guess that sleep disturbances are closely related to the onset of PCOS with "metabolic type".3.The current studies offer genetic support for the association between sleep and PCOS and its metabolic side effects,,but further studies are required to explain the underlying processes and mechanisms of these association.