Association Study Between Clock Genes And Parkinson’s Disease And Accompanying Depression And Sleep Disturbances

ObjectiveCircadian rhythm disturbance has been implicated in depression and sleep disturbances.The polymorphisms of clock genes, Cry1, Cry2, and Tef, are associated with depression.Tef has been suggested to be associated with restless legs syndrome and slow wavessleep in patients with sleep disorders. The objective of the present study was to validatewhether polymorphisms of Cry1rs2287161, Cry2rs10838524, and Tef rs738499areassociated with major depressive disorder (MDD) and Parkinson’s disease (PD), and toexplore the genetic susceptibility of depression in PD (dPD) and sleep disturbances inPD patients, meanwhile, to analyze factors influencing dPD and sleep quality.Method408subjects with PD (including120patients with depression [dPD] and140non-depressive patients [n-dPD]),105subjects with MDD and485control subjectsparticipated in this case-control study. The frequency of polymorphisms of Cry1rs2287161, Cry2rs10838524and Tef rs738499was screened by polymerase chainreaction-restriction fragment length polymorphism (PCR-RFLP). PD patients wereassessed with Unified PD Rating Scale-Part-III (UPDRS-III), Hoehn-Yahr stages (H-Y),Daily levodopa equivalent dose (LED),24-item Hamilton Depression Scale (HAMD),Parkinson Disease Sleep Scale (PDSS) and Mini-Mental State Examination (MMSE).MDD patients and controls were assessed with HAMD and MMSE. Statistical analysiswas performed with the SPSS version13.0and the SHEsis program. Results1. There was no difference in age and gender between MDD and control group(P0.05). The HAMD scores of MDD cases were significantly higher than thoseof controls (x2=-16.43, P<0.01). MMSE scores of MDD cases were significantlylower than those of controls (x2=-16.08, P<0.01). There was no difference in ageand gender between dPD and control group (P0.05). The HAMD scores of dPDcases were significantly higher than those of controls (x2=-17.32, P<0.01).MMSE scores of dPD cases were significantly lower than those of controls (x2=-11.79, P<0.01). There was no difference in age between n-dPD and controlgroup (P0.05). Males in n-dPD group were more than control group (x2=-4.61,P0.01). The HAMD scores of n-dPD cases were significantly higher than thoseof controls (x2=-9.05, P<0.01). MMSE scores of n-dPD cases were significantlylower than those of controls (x2=-9.59, P<0.01). There were significantdifferences in gender, duration, HAMD scores, PDSS scores, MMSE scores,H-Y, and UPDRS-III scores between n-dPD and dPD group (all P<0.05). Nodifference was found in age and LED between the two groups (all P>0.01).2. In all the participants, the genotypes of Cry1rs2287161were CC, CG and GG,and the genotypes of Cry2rs10838524were AA and AG, and the genotypes ofTef rs738499were TT, TG and GG. The distribution of genotypes for each SNPwas fitting with Hardy-Weinberg Equilibrium in each group (all P>0.05).3. Patients with the CC genotype of Cry1rs2287161had significantly higher scoresof HAMD (x2=-2.49, P=0.013) and UPDRS-III (x2=-2.24, P=0.025), and lowerscore of PDSS (x2=-3.04, P=0.002) than those with CG or GG genotypes.Patients with the TT genotype of Tef rs738499had significantly higher scores ofHAMD (x2=-3.38, P=0.001), H-Y (x2=-2.09, P=0.037) and UPDRS-III (x2=-2.54,P=0.011), and lower score of PDSS (x2=-4.39, P=0.000) than those with CG or GG genotypes. Patients with the AA genotype of Cry2rs10838524had nodifferent clinical data to patients with the AG genotypes.4. Univariate Logistic regression analysis showed that gender, age or Cry2rs10838524had no relationship with MDD, however, MMSE (OR=2.1795%CI:1.87~2.44,P=0.000), the CC genotype of Cry1rs2287161(OR=1.79,95%CI:1.10~2.91,P=0.019) and the TT genotype of Tef rs738499(OR=2.43,95%CI:1.42~3.84,P=0.001) were associated with MDD. Multivariate Logistic regression analysisshowed that MMSE (OR=2.38,95%CI:2.08~2.78, P=0.000), the CC genotype ofCry1rs2287161(OR=4.17,95%CI:1.10~2.91, P=0.001) and the TT genotype of Tefrs738499(OR=10.88,95%CI:4.45~26.61, P=0.000) were independent risk factorsof MDD, meanwhile, the CC genotype of Cry1rs2287161and the TT genotype ofTef rs738499had a negative interaction (OR=0.17,95%CI:0.04~0.75, P=0.000) inthe onset of MDD.5. Univariate Logistic regression analysis showed that age or Cry2rs10838524had norelationship with PD, however, male (OR=1.56,95%CI:1.22~2.08, P=0.001),MMSE (OR=1.52,95%CI:1.38~1.66, P=0.000), HAMD(OR=2.05,95%CI:1.83~2.31, P=0.000), the CC genotype of Cry1rs2287161(OR=1.36,95%CI:1.02~1.80, P=0.034) and the TT genotype of Tef rs738499(OR=1.48,95%CI:1.12~1.96, P=0.005) were associated with PD. Multivariate Logistic regressionanalysis showed that male (OR=2.14,95%CI:1.34~3.40, P=0.001), MMSE(OR=1.33,95%CI:1.18~1.46, P=0.000), HAMD (OR=2.13,95%CI:1.87~2.43,P=0.000) and the TT genotype of Tef rs738499(OR=1.86,95%CI:1.14~3.01,P=0.012) were independent risk factors of PD.6. Univariate Logistic regression analysis showed that age or Cry2rs10838524had norelation with dPD, however, female (OR=2.19,95%CI:1.31~3.67, P=0.003), diseaseduration (OR=1.08,95%CI:1.02~1.13, P=0.007), MMSE (OR=1.15,95%CI: 1.05~1.26, P=0.002), PDSS (OR=1.07,95%CI:1.05~1.09，P=0.000), H-Y (OR=2.87,95%CI:2.01~4.08，P=0.000), UPDRS-III (OR=1.08,95%CI:1.06~1.10, P=0.000),the CC genotype of Cry1rs2287161(OR=1.75,95%CI:1.13~2.71, P=0.025) and theTT genotype of Tef rs738499(OR=1.80,95%CI:1.06~3.07, P=0.030) wereassociated with dPD. Multivariate Logistic regression analysis showed that female(OR=2.63,95%CI:1.23~5.60, P=0.012), PDSS (OR=1.07,95%CI:1.05~1.09,P=0.000) and UPDRS-III (OR=1.07,95%CI:1.03~1.11, P=0.001) were independentrisk factors of dPD. The CC genotype of Cry1rs2287161and the TT genotype of Tefrs738499were of no significance to dPD (P0.05).7. PD patients with the CC genotype of Cry1rs10838524had significantly lower totalscores of PDSS (x2=-3.04, P=0.002) and lower scores of item8(x2=-2.81, P=0.005)than carriers with the CG or GG genotype. PD patients with the TT genotype of Tefrs738499also displayed significantly lower total scores of PDSS (x2=-4.17, P=0.000)and lower scores of item1,4,6,10,12,13(all P0.05) than carriers with the TG orGG genotype. There was no significant association of Cry2rs10838524with the totalor item scores of PDSS (all P0.05).8. Spearman’s rank correlation showed that the total PDSS scores were associated withgender (r=-0.123, P=0.013), disease duration (r=-0.190, P=0.000), HAMD scores(r=-0.526, P=0.000), MMSE scores (r=0.134, P=0.009), UPDRS-III (r=-0.252,P=0.000), H-Y (r=-0.298, P=0.000), Cry1rs2287161(r=0.151, P=0.002) and Tefrs738499(r=0.218, P=0.000).9. Stepwise linear regression showed that polymorphism of Tef rs738499could explain5%of the variance of PDSS scores, and the polymorphism of Cry1rs2287161couldexplain1.1%of the variance of PDSS scores. After adjusted by gender, diseaseduration, H-Y, UPDRS-III, HAMD and MMSE, HAMD, H-Y and Tef rs738499were the main influencing factors of PDSS. Tef rs738499still could explain1.5%of the variance of PDSS scores (P=0.003), but the association between Cry1rs2287161and PDSS scores became non-significant.Conclusion1. These results suggest that the polymorphisms of Cry1rs2287161and Tef rs738499are associated with MDD.2. The polymorphisms of Cry1rs2287161and Tef rs738499are not associated withdPD. The risk factors of dPD are female, poor sleep quality and sever motorsymptoms.3. The polymorphism of Tef rs738499relates to PD.4. The polymorphism of Tef rs738499relates to sleep disturbances in PD. The riskfactors of sleep disturbances in PD are sever depression symptom, high H-Y and theTT genotype of Tef rs738499.5. There was no association of Cry2rs10838524with MDD, PD, dPD or sleepdisturbances in PD.