The Association Analysis Between Nogo-related Genes And Parkinson’s Disease

Background: Parkinson’s Disease(PD)is the second major neurodegenerative disease,mainly manifested as resting tremor,bradykinesia,muscle rigidity,and abnormal posture and gait.The specific pathogenic mechanism of PD is still unclear,but it is generally believed to be caused by aging,genetic factors and environmental factors.Among them,genetic factors have been proved to be widely involved in the occurrence,development and prognosis of PD.Our previous research found that the Nogo family-related gene—NUS1,was associated with the pathogenesis of PD.In addition,further studies have found that Nogo family-related may be related to axon growth and synaptic plasticity.However,the studies about the genetics of the Nogo family in PD is rare.Therefore,Aim: This study aimed to preliminarily explore the association between Nogo family-related genes and PD in the Chinese population.Methods: The Nogo family-related genes were screened by literature query,and the genetic variation analysis of Nogo family-related genes was performed via the PD genetics database of PD-MDCNC(3959 PD patients and 2931 healthy controls).All patients were divided into sporadic earlyonset Parkinson’s disease & Familial Parkinson’s disease(s EOPD & FPD)cohort and sporadic late-onset PD(s LOPD)cohort according to age at onset and family history.The patients and healthy controls in s EOPD &FPD cohort and s LOPD cohort were separately conducted by WES and WGS.Rare and common variants in the coding region of Nogo familyrelated genes were screened according to the Minor Allele Frequency(MAF).Rare variants(MAF<0.01)in the coding region of Nogo familyrelated genes were subjected to Gene-based Burden Analysis;common variants in the coding regions of Nogo family-related genes(MAF≥0.01)were subjected to Logistic regression analysis.Finally,genotypephenotype association analysis of MTOR gene was performed by linear regression and Logistic regression.Results: A total of 17 Nogo family-related genes were included in this study,containing three categories,namely ligand,receptors and signaling pathway.In the s EOPD & FPD cohort,a total of 1006 rare variants were found in Nogo family-related genes,407 of them predicted to be Damaging(Dmis),and 26 Loss of Function(Lo F).In the s LOPD cohort,751 rare variants were found,302 of them predicted to be Dmis and 10 Lo Fs.In the rare variant analysis,the deleterious variant of Nogo receptor genes(FDRP=0.044,OR=0.815),and the missense mutation of LILRB1 gene(FDRP=0.034,OR=1)and MTOR gene(FDR-P=0.034,OR=1.866)was significantly different between PD patients and healthy controls after False Discovery Rate(FDR)correction.In the common variant analysis,a total of 219 common variants were found in the s EOPD & FPD cohort,and 2256 common variants were found in the s LOPD cohort.Besides,all common variants were not statistically different between PD patients and healthy controls.Finally,genotype-phenotype association analysis of MTOR gene showed the PD patients with MTOR variants had slighter motor symptoms and severer dyskinesia.Conclusion: Rare missense variants of MTOR gene may increase the risk of PD,and the deleterious variants of Nogo receptor genes may reduce the risk of PD.However,the common variants of Nogo family-related genes are not significantly associated with PD,and the genotype of MTOR gene is associated with motor symptoms and dyskinesia of PD.