Effects of genetic rare variants on Parkinson's disease in the Korean population

다국어 초록 (Multilingual Abstract)

Background: The genetic background of a disease is usually explained by either rare mutations in a disease-causing gene or common susceptibility alleles that increase risk for a disease. A number of causative or susceptibility genes have been discovered for familial and idiopathic Parkinson’s disease. Although mutations in PARK2 are known to be the most common autosomal recessive gene for early onset Parkinson’s disease, these mutations are rare in Asians. Moreover, there is still much debate about whether a single heterozygous PARK2 mutation is a risk factor for Parkinson’s disease. There are very few patient-control gene-dosage studies for PARK2, and notably there has been only 1 study on the Asian population. Mutation in the glucocerebrosidase (GBA) gene is a causal mutation for Gaucher’s disease; however, many different ethnic populations have a heterozygous carrier of this mutation, which has a 3-fold higher risk for Parkinson’s disease. There have been no studies on the effect of the GBA mutation on Parkinson’s disease in the Korean population, although given that Gaucher’s disease is extremely rare in Korea, a heterozygous mutation of GBA might not be a risk allele. The purpose of this study was to investigate whether rare variants of GBA or PARK2 are linked to Parkinson’s disease in the Korean population. Methods: The frequency of the GBA mutation was compared between patient and control populations in order to determine whether a heterozygous mutation in GBA is associated with Parkinson’s disease in the Korean population. Common GBA mutations in the Korean population were also determined. GBA mutations were assessed in 277 PD patients and 291 normal control subjects. All exons of the GBA gene were analyzed in all patients and in 100 normal control subjects. Exons 2 and 5？11, where mutations were observed in the patient population, were further analyzed in 191 additional normal control subjects. To investigate whether a single heterozygous mutation of PARK2 is associated with Parkinson’s disease, the gene dosage of all exons of PARK2 was analyzed in patients with early onset and familial Parkinson’s disease and control subjects. Dosage analysis of mutations in the PARK2 gene was performed in 188 early onset or familial Parkinson’s disease patients and 191 normal control subjects by using real-time polymerase chain reaction. In patients who showed a heterozygous gene-dosage mutation, sequence analysis was performed to exclude the possibility of complex heterozygous mutations. Results: GBA mutation analysis revealed 5 heterozygous mutations, N188S, P201H, R257Q, S271G, and L444P, in 9 (3.2%) Parkinson’s disease patients. No GBA mutations were detected in the normal control group (p < 0.01; odds ratio, 20.6; 95% confidence interval, 1.2？356.4). The patients with a heterozygous GBA mutation showed a significantly earlier onset of disease than the patients without the mutation (48.6 ± 11.9 vs. 57.9 ± 13.5; p < 0.05; Mann？Whitney test). Analysis of the PARK2 mutation revealed that 21 (11.2%) patients had a mutation in PARK2. Of them, five (23.8%) patients had compound heterozygous mutations and 13 (61.9%) had a heterozygous mutation. Among 29 mutated alleles, one small sequence variation was found (3.4%). Gene-dosage mutation accounted for most of the total mutations found (96.6%), and all of the heterozygous mutations were gene-dosage mutations. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD than in the controls. Conclusion: Rare genetic variant mutations of the GBA or PARK2 genes, implicated as a background for Parkinson’s disease, are also risk factors for Parkinson’s disease in the Korean population.