Subject(s)
Essential Tremor/genetics , Genetic Predisposition to Disease/genetics , Membrane Glycoproteins/genetics , Mutation/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Asian People/genetics , Essential Tremor/ethnology , Female , Genetic Association Studies , Humans , Male , Middle Aged , Young AdultABSTRACT
Objective. COQ2 mutations have been reported in Japanese multiple system atrophy (MSA) patients. We examined the role of COQ2 in patients with dementia and essential tremor (ET), two common neurodegenerative conditions. Materials & Methods. A total of 2064 subjects, including 560 patients with dementia, 466 patients with ET, and 1038 healthy controls, were included. Genotyping for the COQ2 V393A (T>C) was carried out. Odds ratio (OR) adjusted by age and gender, together with 95% confidence interval (CI), was reported by means of logistic regression. Results. The frequency of the polymorphic variant V393A heterozygous (T/C) was 2.7% in dementia, 1.1% in ET, and 2.5% in controls (OR = 0.70, 95% confidence interval is 0.29-1.72 for dementia, and OR = 0.47, 95% confidence interval is 0.17-1.31, p = 0.1217 for ET). There was no significant association between V393A variant with dementia and ET. Conclusion. There was no significant association between V393A variant with dementia and ET. COQ2 gene is unlikely to play a significant role in patients with dementia or ET in our population.
ABSTRACT
Overlapping neurodegenerative pathologies (including Alzheimer's disease, AD) have been described in Parkinson's disease (PD) patients with leucine-rich repeat kinase-2 (LRRK2) mutations. We analyzed a LRRK2 PD (R1628P) risk variant in a group of 885 subjects comprising of AD and controls. The frequency of the R1628P allele was higher in AD compared to controls (3.5% vs. 1.6%, OR 2.3, 95 CI 1.2-4.4, p=0.018). In vitro, the mean percentage of apoptosis and cell death observed for the R1628P transfected human cell lines was higher compared to wild type 21.8 ± 1.9, vs. 17.1 ± 1.3, p<0.05, 30.2 ± 2.2 vs. 25.7 ± 1.3, p<0.05). The LRRK2 R1628P variant increases the risk of AD in our population and our in vitro findings suggest that it is a functional variant and predisposes to apoptosis.
Subject(s)
Alzheimer Disease/genetics , Apoptosis/genetics , Protein Serine-Threonine Kinases/genetics , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Cells, Cultured , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Parkinson Disease/genetics , TransfectionABSTRACT
In a case control study involving 484 study subjects, we showed that the CALHM1 allele (13.5% vs 16.7%) and genotype frequency was not significantly different between Alzheimer's disease (AD) and controls. Logistic regression analysis did not reveal any interaction between ApoE4 allele and CALHM1 allele.
Subject(s)
Alzheimer Disease/genetics , Calcium Channels/genetics , Membrane Glycoproteins/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Aged , Aged, 80 and over , Apolipoprotein E4/genetics , Asia/epidemiology , Asia/ethnology , Case-Control Studies , Female , Gene Frequency , Genome-Wide Association Study/methods , Genotype , Humans , Logistic Models , Male , Middle AgedABSTRACT
We showed that the frequency of a LRRK2 variant (c.4883G > C, R1628P) was higher in Parkinson's disease (PD) compared to controls (8.4 vs. 3.4%, P = 0.046, OR 2.5, 95% CI 1.1-5.6). In the multivariate logistic regression (with adjustments made for the effect of age, age of onset, and gender), the heterozygous R1628P genotype was associated with an increased risk of PD compared to controls (OR 3.3, 95% CI 1.4- 7.9, P = 0.007). We provided an independent confirmation that the R1628P variant increases the risk of PD among Chinese.
Subject(s)
Genetic Predisposition to Disease , Parkinson Disease/ethnology , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Adult , Aged , Aged, 80 and over , Case-Control Studies , China , Female , Genetic Variation , Genotype , Heterozygote , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , RiskSubject(s)
Genetic Predisposition to Disease/genetics , Glucosylceramidase/genetics , Mutation/genetics , Parkinson Disease/enzymology , Parkinson Disease/genetics , Adult , Age Distribution , Aged , Aged, 80 and over , Asian People/genetics , Brain/metabolism , Brain/physiopathology , Case-Control Studies , DNA Mutational Analysis , Female , Gene Frequency , Genetic Testing , Genotype , Humans , Male , Middle Aged , Parkinson Disease/ethnology , Risk Factors , Sex DistributionABSTRACT
Parkinson's disease (PD) is a complex neurodegenerative disorder whose aetiologies are largely unknown. To date, mutations in six genes have been found causal for some rare familial forms of the disease and common variation within at least three of these is associated with the more common sporadic forms of PD. LRRK2 is the most recently identified familial PD gene, although its role in sporadic disease is unknown. In this study, we have performed the first comprehensive evaluation of common genetic variation within LRRK2 and investigated its contribution to risk of sporadic PD. We first characterized the linkage disequilibrium within LRRK2 using a panel of densely spaced SNPs across the gene. We then identified a subset of tagging-SNPs (tSNP) that capture the majority of common variation within LRRK2. Both single tSNP and tSNP haplotype analyses, using a large epidemiologically matched sporadic case-control series comprising 932 individuals, yielded significant evidence for disease association. We identified a haplotype that dramatically increases disease risk when present in two copies (OR=5.5, 95%CI=2.1-14.0, P=0.0001). Thus, we provide the first evidence that common genetic variation within LRRK2 contributes to the risk of sporadic PD in the Chinese population.
Subject(s)
Genetic Predisposition to Disease , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Adult , Aged , Aged, 80 and over , Asian People/genetics , Female , Gene Frequency , Haplotypes , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Linkage Disequilibrium , Male , Middle Aged , Parkinson Disease/epidemiology , Risk FactorsABSTRACT
A common heterozygous leucine-rich repeat kinase 2 (LRRK2) mutation 6055G > A transition (G2019S) accounts for about 3-7% of familial Parkinson's disease (PD) and 1-1.6% sporadic PD in a number of European populations. To determine the prevalence of the G1019S mutation in our Asian population, we conducted genetic analysis of this mutation in 1000 PD and healthy controls. The G2019S mutation was not detected in any of our study subjects. The prevalence of G2019S mutation is rare (< 0.1%) in our population, suggesting that occurrence of this mutation may vary amongst different ethnic races. This has important clinical implication when implementing guidelines for genetic testing.
