Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel–Haenszel procedure used to estimate odds ratios across centers. All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non–Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non–Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case–control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case–control populations, we found that a SNP in α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10⁻¹⁰). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D′>0.9) spanning ∼120 kb. A tight LD group (r²>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0×10⁻⁹–1.7×10⁻¹¹). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.

Parkinson disease (PD), characterized by tremor, rigidity, bradykinesia, and postural instability, is the second most common neurodegenerative disease after Alzheimer disease, with usual onset in late adulthood, that is, after age 50 years.The prevalence of PD is estimated to be 0.3% in the general population and 1% in individuals older than 60 years.¹ Although SNCA, LRRK2, UCHL-1, PARK2, PINK1, and DJ-1 have been identified as the causative genes for familial PD,² patients with PD with pathogenic mutations in these genes are rare. Most cases of PD are sporadic and the etiologies poorly understood. A population-based study coupled with genealogic information demonstrated that the estimated risk ratio for PD in siblings of patients with PD was significantly high (λs = 6.7), which suggests that genetic factors substantially contribute to the development of sporadic PD.³ To elucidate susceptibility genes for sporadic PD, numerous case-control association studies using the analyses of single nucleotide polymorphisms have been conducted under the common disease–common variants hypothesis; however, only a few consistent findings have been observed.⁴ Recently, polymorphisms of SNCA, a major component of Lewy bodies, a pathologic hallmark of PD, have been reported to be associated with sporadic PD (odds ratio [OR], 1.4-2.0).^5,6

Objective: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. Methods: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.