Xue-Ye Mao

Association of GWAS loci with PD in China

Genome‐wide association studies (GWAS) have identified numerous single‐nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinsons disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case–control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS‐linked data and research on ethnic specific effect of common variants.

Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China

Mutations in GBA gene have been reported to be in patients with Parkinsons disease (PD) from different ethnic populations, including Taiwanese Chinese. To explore whether mutation in GBA is also associated with PD in Mainland China, we have now a case control study. The occurrence of the GBA L444P mutation was analyzed in an independent cohort of PD patients and controls from Mainland China. This mutation was present in 20/616 (3.2%) of PD compared with 1/411 (0.2%) of controls (odds ratio, OR=13.76, 95% Confidence interval, CI: 1.84-102.92, p=0.001). All carriers harbored the heterozygous genotype. In a subset analysis, the frequency of this mutation was higher both in early onset (EOPD) and late onset PD (LOPD) than in controls. However, no difference in clinical characteristics, such as gender, age at onset, onset symptoms, Hoehn-Yahr stage and UPDRS, was found between L444P carriers and non-carriers. In addition, we also explored the potential relationship between GBA L444P mutation and LRRK2 G2385R and R1628P variants in patients with PD. But no association was found, either. In conclusion, our data suggest that the GBA L444P mutation plays an important role in the development of PD also in Han-Chinese patients from Mainland China.

LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China.

Mutations in LRRK2, the gene that encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinsons disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han‐Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60–6.17, P < 0.01]. Considering the age at onset, this difference was found only in late‐onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90–7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han‐Chinese population.

Lack of evidence for association of a UCH-L1 S18Y polymorphism with Parkinson's disease in a Han-Chinese population.

Mutation in UCH-L1 has been reported as a rare cause of autosomal dominant Parkinsons disease (PD). A S18Y polymorphism in the same gene has been associated with sporadic PD. We investigated the frequency of this polymorphism among the Han-Chinese ethnic population in a case-control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR-restriction fragment length polymorphism analysis. We did not observe any difference in allele or genotype frequencies between the cases and the controls (P>0.05). Our results do not support a role for this variant in sporadic PD.

Genetic Association Study betweenSTK39 and CCDC62/HIP1R and Parkinson’s Disease

Background The first large-scale meta-analysis of published genome-wide association studies (GWAS) in Parkinson’s disease (PD) identified 5 new genetic loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). Very recently, a large-scale replication and heterogeneity study also reported that STK39 and CCDC62/HIP1R increased risk of PD in Asian and Caucasian populations. However, their roles still remain unclear in a Han Chinese population from mainland China. Methods We examined genetic associations of STK39 rs2102808 and CCDC62/HIP1R rs12817488 with PD susceptibility in a Han Chinese population of 783 PD patients and 725 controls. We also performed further stratified analyses by the age of onset and accomplished in-depth clinical characteristics analyses between the different genotypes for each locus. Results No significant differences were observed in the minor allele frequency (MAF) among cases and controls at the two loci (STK39 rs2102808: OR = 1.06, 95% CI = 0.91, 1.23, P = 0.467; CCDC62/HIP1R rs12817488: OR = 0.88, 95% CI = 0.76, 1.01, P = 0.072). Subgroup analyses by the age of onset also showed no significant differences among different subgroups of the two loci. In addition, minor allele carriers cannot be distinguished from non-carriers based on their clinical features at the two loci. Conclusions We are unable to demonstrate the association between STK39 and CCDC62/HIP1R and PD susceptibility in a Han Chinese population from mainland China. Additional replication studies in other populations and functional studies are warranted to better validate the role of the two new loci in PD risk.

Mutations in GBA and risk of Parkinson's disease: a meta-analysis based on 25 case-control studies.

Abstract The association between glucocerebrosidase (GBA) mutations and Parkinson’s disease (PD) is attracting increased attention worldwide. Results from previous studies on the association of GBA mutations with PD in different ethnicities remain contradictory. In order to derive a more comprehensive understanding of the relationship between the most common GBA mutations, L444P and N370S and PD susceptibility, an updated meta-analysis was performed by searching PUBMED, EMBASE, MEDLINE, and EBSCO databases. Twenty five studies including 9, 599 cases and 13, 541 controls were collected in the end. The summary of odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using fixed- and random-effects models, when appropriate. Overall, our meta-analysis provided evidence that both were risk factors associated with increased PD susceptibility. When stratified by ethnicities, the associations varied among different ethnical origins.

SNCA rs356219 variant increases risk of sporadic Parkinson's disease in ethnic Chinese

Alpha‐synuclein gene (SNCA) polymorphisms have been associated with Parkinsons disease (PD). A recently published genome‐wide association study (GWAS) meta‐analysis from the USA and Europe found a strong association between SNCA rs356219 and PD. Considering the population‐specific heterogeneity, we investigated the role of SNCA rs356219 as PD susceptibility in a large Han Chinese population of 685 patients and 569 controls. The SNCA rs356219‐G allele was found to increase the risk to develop PD (OR = 1.81, 95% CI: 1.54–2.13, P = 5.71E−13). The meta‐analysis revealed that the frequency of AG + GG genotypes higher in PD than in control subjects (OR = 1.85, 95% CI: 1.56–2.19, P = 0.00001) in the Asian population. PD patients with AG + GG genotypes were associated with earlier age at onset compared with those with AA genotype. No such significant association was observed in the clinical presentation for gender, age at onset, and onset symptoms. Our study provides strong support for the susceptibility role of SNCA rs356219 in sporadic PD in a Han Chinese population from mainland China and the meta‐analysis also revealed a similar finding in the Asian population.

Genetic analysis of LRRK2 A419V variant in ethnic Chinese

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common causes of autosomal dominant and sporadic forms of Parkinsons disease (PD). The A419V variant has been suggested to be a potential risk variant but its role among Chinese is unclear. We genotyped LRRK2 A419V variant to investigate the association with risk of PD. A total of 1314 subjects comprising 729 patients with PD and 585 controls were genotyped. Twenty-two (3.0%) patients were heterozygous carriers for the A419V variant, and the frequency was higher compared with controls (0.7%, p = 0.003). The association was seen among the younger age group (early onset PD patients vs. controls: p = 0.0005), but was not significant among the older age group (late onset PD patients vs. controls: p = 0.17). We showed a significant association of LRRK2 A419V variant among early onset PD in the ethnic Han Chinese population but not among late onset PD. Further replication studies in additional Chinese and other Asian cohorts will be important to address its potential pathophysiologic role.

MTHFR C677T variant reduces risk of sporadic Parkinson's disease in ethnic Chinese

Genetic variability of methylenetetrahydrofolate reductase (MTHFR) may be associated with Parkinsons disease (PD). Its role in ethnic Chinese population is still unclear. Our study aimed to investigate whether MTHFR C677T variation was linked to PD risk in a Han Chinese population from mainland China.

GSK3β reduces risk of sporadic Parkinson's disease in ethnic Chinese.

Genetic variability of glycogen synthase kinase‐3β (GSK3β) may be linked to Parkinsons disease (PD). Its role in ethnic Chinese population is still unclear. We examined the association between GSK3β variation and PD in a Han Chinese population from mainland China. Using a case–control methodology, we genotyped the single nucleotide polymorphism (SNP) in GSK3β (rs334558) to investigate the association with risk of PD. A total of 1,280 ethnic Han Chinese study subjects comprising 761 sporadic PD patients and 519 controls were recruited. The T allele of a promoter SNP rs334558 was found to reduce the risk of PD (OR = 0.82, 95% CI: 0.696–0.960, P = 0.014). Patients with CT + TT genotypes have a reduced risk of PD compared to those with CC genotype (OR = 0.61, 95% CI: 0.477–0.776, P = 6.09E−5). In addition, we demonstrated that CT + TT subjects cannot be distinguished from CC subjects based on their clinical features. Our data suggest that rs334558 variant in GSK3β reduces the risk of PD in a Han Chinese population from mainland China. Further studies of large series of subjects are necessary to fully elucidate the true role of GSK3β in PD.