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Manu Sharma,
John P A Ioannidis,
Jan O Aasly,
Grazia Annesi,
Alexis Brice,
Lars Bertram,
Maria Bozi,
Maria Barcikowska,
David Crosiers,
Carl E Clarke, [......],
Christine Van Broeckhoven,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Harumi S Yomono,
Kuo-Chu Yueh,
Yi Zhao,
Thomas Gasser,
Demetrius Maraganore,
Rejko Krüger
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
Journal of Medical Genetics 11/2012; 49(11):721-726. · 6.36 Impact Factor
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[show abstract]
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ABSTRACT: The single-nucleotide polymorphism (SNP) rs5174 of the low-density lipoprotein receptor-related protein 8 (LRP8) gene has been linked to decreased risk for Parkinson's disease (PD) on Caucasian populations. However, this association has not been proven in Han Chinese populations.
A total of 378 unrelated Han patients with PD from the Department of Neurology, West China Hospital of Sichuan University and 274 unrelated Han healthy controls (HCs) from the same region were included in this study. SNPs rs5174 and rs3820198 were genotyped using the Sequenom iPLEX Assay technology.
No significant difference was found in the genotype and minor allele frequencies (MAFs) of SNPs rs5174 and rs3820198 between the PD and HC groups, the early-onset PD and HC groups, the late-onset PD and HC groups, as well as the early-onset PD and late-onset PD groups.
This report is the first one on the lack of association of the LRP8 SNPs rs5174 and rs3820198 with PD in Han Chinese population. Together with a Japanese study, the results indicate that the variants within the LRP8 gene do not contribute to the risk of developing PD in Asian populations.
Neurological Research 09/2012; 34(7):725-9. · 1.52 Impact Factor
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Manu Sharma,
John P A Ioannidis,
Jan O Aasly,
Grazia Annesi,
Alexis Brice,
Christine Van Broeckhoven,
Lars Bertram,
Maria Bozi,
David Crosiers,
Carl Clarke, [......],
Hiroyuki Tomiyama,
Ryan J Uitti,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Kuo-Chu Yueh,
Yi Zhao,
Thomas Gasser,
Demetrius Maraganore,
Rejko Krüger
Neurology 08/2012; 79:1-9. · 8.31 Impact Factor
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Manu Sharma,
John P A Ioannidis,
Jan O Aasly,
Grazia Annesi,
Alexis Brice,
Christine Van Broeckhoven,
Lars Bertram,
Maria Bozi,
David Crosiers,
Carl Clarke, [......],
Hiroyuki Tomiyama,
Ryan J Uitti,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Kuo-Chu Yueh,
Yi Zhao,
Thomas Gasser,
Demetrius Maraganore,
Rejko Krüger
[show abstract]
[hide abstract]
ABSTRACT: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
Neurology 07/2012; 79(7):659-67. · 8.31 Impact Factor
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Ikuko Mizuta,
Tatsuhiko Tsunoda, Wataru Satake,
Yuko Nakabayashi,
Masahiko Watanabe,
Atsushi Takeda,
Kazuko Hasegawa,
Kenji Nakashima,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Tatsushi Toda
[show abstract]
[hide abstract]
ABSTRACT: Parkinson’s disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic
neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes
identified α-synuclein (SNCA) as a susceptibility gene for sporadic PD (P=1.7×10−11). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P=0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes,
but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P<0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent
sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P=7.1×10−5; recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of
CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests
that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA.
Human Genetics 04/2012; 124(1):89-94. · 5.07 Impact Factor
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Manu Sharma,
Demetrius M Maraganore,
John P A Ioannidis,
Olaf Riess,
Jan O Aasly,
Grazia Annesi,
Nadine Abahuni,
Anna Rita Bentivoglio,
Alexis Brice,
Christine Van Broeckhoven, [......], Wataru Satake,
Peter A Silburn,
Jessie Theuns,
Tatsushi Toda,
Hiroyuki Tomiyama,
Ryan J Uitti,
Karin Wirdefeldt,
Zbigniew Wszolek,
Thomas Gasser,
Rejko Krüger
[show abstract]
[hide abstract]
ABSTRACT: Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies.
Neurobiology of aging 07/2011; 32(11):2108.e1-5. · 5.94 Impact Factor
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Rejko Krüger,
Manu Sharma,
Olaf Riess,
Thomas Gasser,
Christine Van Broeckhoven,
Jessie Theuns,
Jan Aasly,
Grazia Annesi,
Anna Rita Bentivoglio,
Alexis Brice, [......],
Owen A Ross, Wataru Satake,
Peter A Silburn,
Eng King Tan,
Tatsushi Toda,
Hiroyuki Tomiyama,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Demetrius M Maraganore
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[hide abstract]
ABSTRACT: High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
Neurobiology of aging 03/2011; 32(3):548.e9-18. · 5.94 Impact Factor
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Hao Sun, Wataru Satake,
Changjun Zhang,
Yoshitaka Nagai,
Youyong Tian,
Shouzhi Fu,
Jiankun Yu,
Yaping Qian,
Yuan Qian,
Jiayou Chu,
Tatsushi Toda
[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism-predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree.
Journal of Human Genetics 02/2011; 56(4):330-4. · 2.57 Impact Factor
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Rinshō shinkeigaku = Clinical neurology. 11/2010; 50(11):864.
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Wataru Satake,
Yuko Nakabayashi,
Ikuko Mizuta,
Yushi Hirota,
Chiyomi Ito,
Michiaki Kubo,
Takahisa Kawaguchi,
Tatsuhiko Tsunoda,
Masahiko Watanabe,
Atsushi Takeda, [......],
Kazuko Hasegawa,
Fumiya Obata,
Takeo Yoshikawa,
Hideshi Kawakami,
Saburo Sakoda,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Yusuke Nakamura,
Tatsushi Toda
[show abstract]
[hide abstract]
ABSTRACT: To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.
Nature Genetics 11/2009; 41(12):1303-7. · 35.53 Impact Factor
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Ikuko Mizuta,
Tatsuhiko Tsunoda, Wataru Satake,
Yuko Nakabayashi,
Masahiko Watanabe,
Atsushi Takeda,
Kazuko Hasegawa,
Kenji Nakashima,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Tatsushi Toda
[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes identified alpha-synuclein (SNCA) as a susceptibility gene for sporadic PD (P = 1.7 x 10(-11)). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P = 0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes, but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P < 0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P = 7.1 x 10(-5); recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA.
Human Genetics 09/2008; 124(1):89-94. · 5.07 Impact Factor
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Wataru Satake,
Ikuko Mizuta,
Satoko Suzuki,
Yuko Nakabayashi,
Chiyomi Ito,
Masahiko Watanabe,
Atsushi Takeda,
Kazuko Hasegawa,
Saburo Sakoda,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Tatsushi Toda
[show abstract]
[hide abstract]
ABSTRACT: A genetic association between the fibroblast growth factor 20 (FGF20) gene and Parkinson's disease has been found by the pedigree disequilibrium test. This association, however, was not replicated by a case-control association study. In order to clarify the association between the FGF20 gene and Parkinson's disease, we attempted to replicate this association by a case-control association study using a large number of Japanese samples (1388 patients and 1891 controls). rs1721100 exhibited a significant difference in allele C versus G (P=0.0089), and in genotype CC+CG versus GG (P=0.0053). Haplotype association analysis showed that haplotype 2 was the protective haplotype for Parkinson's disease (permutation-P=0.0075). These results suggest that the FGF20 gene is a susceptibility gene for Parkinson's disease in the Japanese population.
Neuroreport 07/2007; 18(9):937-40. · 1.66 Impact Factor
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Ikuko Mizuta, Wataru Satake,
Yuko Nakabayashi,
Chiyomi Ito,
Satoko Suzuki,
Yoshio Momose,
Yoshitaka Nagai,
Akira Oka,
Hidetoshi Inoko,
Jiro Fukae,
Yuko Saito,
Motoji Sawabe,
Shigeo Murayama,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Tatsushi Toda
[show abstract]
[hide abstract]
ABSTRACT: 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 alpha-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0 x 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 approximately 120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0 x 10(-9)-1.7 x 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.
Human Molecular Genetics 05/2006; 15(7):1151-8. · 7.64 Impact Factor
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[hide abstract]
ABSTRACT: Using a meiosis-specific subtracted cDNA library of Schizosaccharomyces pombe, we identified meu14+ as a gene whose expression is upregulated during meiosis. Transcription of meu14+ is induced abruptly after the cell enters meiosis. Its transcription is dependent on the meiosis-specific transcription factor Mei4. In meu14Delta cells, the segregation and modification of the SPBs (spindle pole bodies) and microtubule elongation during meiosis II were aberrant. Meiotic meu14Delta cells consequently produced a high frequency of abnormal tetranucleate cells harboring aberrant forespore membranes and failed to produce asci. In wild-type cells harboring the integrated meu14+-gfp fusion gene, Meu14-GFP first appeared inside the nuclear region at prophase II, after which it accumulated beside the two SPBs at metaphase II. Thereafter, it formed two ring-shaped structures that surrounded the nucleus at early anaphase II. At post-anaphase II, it disappeared. Meu14-GFP appears to localize at the border of the forespore membrane that later develops into spore walls at the end of sporulation. This was confirmed by coexpressing Spo3-HA, a component of the forespore membrane, with Meu14-GFP. Taken together, we conclude that meu14+ is crucial in meiosis in that it participates in both the nuclear division during meiosis II and the accurate formation of the forespore membrane.
Journal of Cell Science 08/2003; 116(Pt 13):2721-35. · 6.11 Impact Factor
