Rare GBA Mutations Analysis In Chinese Han Parkinson Disease Patients

Objective: Parkinson Disease(PD)is one of the most common neurodegenerative diseases,but the pathogenesis of PD is still not clear.Genetic factors especially pharmacogenomics in PD is gathering enhanced attention.Previous studies have demonstrated that GBA is a common genetic risk factor of PD,now we intended to explore the rare variations of GBA gene in Han Chinese PD patients to determine the potential relationships between GBA rare variations and its specific clinical manifestations.Methods: Two hundred and eighty nine PD patients of Han Chinese were enrolled in our study,including 60 early-onset PD patients,229 late-onset PD patients and 348 normal control.DNA were extracted from the peripheral blood of these patients from each group.All samples were tested by next generation sequencing.Then,we compared our identified GBA variants with 1000 Genome Project,Exome Aggregation Consortium,and dp SNP 142 databases,and the variants with a minor allele frequency less than 0.005 were paid attention and then verified by Sanger sequencing.Last,we explored the relationships between GBA rare variations and PD motor and non-motor syndromes.Results: In our study,there are totally 18 novel GBA rare variations carried by 15 patients,which include c.G1081 C,c.C231 G,c.C646 A,c.C94 A,c.G116 T,c.C646 A,c.T1187 G,c.T410 G,c.G626 A,c.G382 C,c.C1243 T,c.T1245-10 G,c.G1506-9A,c.C532 T,c.A667 G,c.C1212 T,c.T420 G,c.A419 G.Eight of these 15 patients are male and the other seven are female;six early-onset and nine late-onset.Among our PD patients,we didn't found any previous reported GBA rare variations(including L444 P,N370S,R120 W,E326K,R131 L,H255Q,W378 G,or V437L).In our genotype-phenotype analysis part,we found that the age at onset was earlier in PD patients with GBA rare variations compared with patients without(P=0.028,student-t test).However,as to the motor syndrome,levodopa-equivalent daily dose,none-motor syndrome and sleep disorders,there are none significant differences between them(P >0.05).Conclusion: In our study,we totally found 18 novel GBA rare variations among 289 Han Chinese PD patients.These identified variations expanded the spectrum of GBA rare variations.However,more researches are need to valid the relationship between these GBA variations and clinical feature.