Genetics of Parkinson's Disease in the Finnish Population

There is much controversy regarding the role of genetics in the etiology of idiopathic PD. The causative genes for familial PD in the Finnish population are unknown. The involvement of complex I, one of the mitochondrial energy generating enzymes of oxidative phosphorylation, in the pathogenesis of PD is well established. However, the role of single mutations in the mitochondrial DNA-encoded complex I (MTND) genes is unclear. We performed familial aggregation and complex segregation analysis (CSA) to analyze the occurrence of PD in families and the mode of inheritance in the Finnish population. The molecular genetic analysis of the α-synuclein and the parkin gene was performed to determine whether mutations in these genes could be detected in Finnish patients with familial PD. The role of mtDNA in PD was investigated by analysis of sequence variation in MTND genes. A family history was obtained for 268 patients with PD and 210 controls selected from the population of the province of northern Ostrobothnia, Finland. A total of 265 nuclear families were included in a CSA with POINTER. The analysis was first carried out for the total data set, and then the heterogeneity between families with early-onset PD (EOPD, proband under 55 years at onset) and families with late-onset PD (LOPD) was examined. Finally, families with more than one affected individual were analyzed separately. The α-synuclein gene was sequenced and 8 previously described mutations in the parkin gene were screened in 22 unrelated patients with familial PD. In addition, 67 controls and 45 patients with sporadic PD were included in the association analysis of polymorphism of the α-synuclein gene. The nonsynonymous to synonymous substitution ratio (Ka/Ks) of the seven MTND genes was determined from 183 Finns. The differences in Ka/Ks of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analyzed using a statistical approach. Altogether 238 patients underwent clinical examination together with haplogroup analysis and the clinical features between patient groups defined by the Ka/Ks ratio were compared. Ten per cent of the probands reported an affected first degree relative, whereas the corresponding frequency was 3.8 per cent in the controls (p=0.01). The relative risk of PD among the first degree relatives of the patients with PD was 2.9 fold (95 % CI 1.3-6.4) and the cumulative incidence of PD by the age of 90 years was 3.3-fold higher among the first degree relatives of the patients than those of the controls. The results of the CSA strongly rejected the sporadic model. Significant heterogeneity was found between the families with EOPD and LOPD, suggesting that major genes have a greater role in EOPD than in LOPD. The CSA of familial PD supported the hypothesis that a major locus was present in this subset, but it was not possible to distinguish between a recessive model with a high penetrance and a dominant model with lower penetrance. The sequence analysis found no mutations or polymorphism in exons 3-7 of the α-synuclein gene. Sequencing of the non-coding exons 1 and 1’, however, revealed three novel alterations in the T10A7 sequence at the 5’ end of exon 1’. The frequencies of the exon 1’ polymorphic genotypes or alleles between patients with familial PD and control subjects revealed no statistically significant differences. No association for sporadic PD was observed. Screening for the parkin gene revealed no mutations in our patients. The haplogroup clusters differed in the Ka/Ks ratio of the MTND genes, the clusters HV and KU having a lower ratio than clusters JT and IWX. Supercluster JTIWX with a high Ka/Ks ratio was more frequent among PD patients and even more frequent among patients with PD who developed dementia. The present study provides evidence that familial aggregation of PD exists in the Finnish population and that it is most likely caused by inherited susceptibility. Genetic heterogeneity exists between families with EOPD and LOPD. The results do not support a role of the α-synuclein gene or point mutations in the parkin gene in familial PD in our sample. Our results indicate that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with increased risk of sporadic PD and progression of the disease to dementia. National Library of Medicine Classification: WL 359 Medical Subject Headings: Parkinson disease/genetics; mutation; point mutation/genetics; polymorphism (genetics); family; family health; genetic heterogeneity; genetics; population; sequence analysis; DNA, mitochondrial