Evaluation of the Role of LRRK2 Gene in Parkinson’s Disease in an East Indian Cohort
TL;DR: It is suggested that LRRK2 has minimal role as a candidate and susceptibility gene in PD pathogenesis among East Indians and any significant allele/ genotype or haplotype associations with PD are unlikely.
Abstract: Leucine rich repeat kinase 2 (LRRK2) gene defects cause Parkinson's disease (PD). Recently, LRRK2 has also been shown by genome wide association (GWA) studies to be a susceptibility gene for the disease. In India mutations in LRRK2 is a rare cause of PD. We, therefore, genotyped 64 SNPs across LRRK2 in 161 control samples and finally studied 6 haplotype tagging SNPs for association-based study on 300 cases and 446 ethnically matched controls to explore the potential role of LRRK2 as a susceptibility gene in PD for East Indians. We did not find any significant allele/ genotype or haplotype associations with PD suggesting that common genetic variants within LRRK2 play limited role in modulating PD among East Indians. In addition, we also screened for the common mutations (viz. p.R1441C, p.R1441G, p.R1441H, p.Y1699C, p.G2019S), and a risk variant common among Asians (p.G2385R) but did not observe any of the above mentioned variants in our cohort. Our study, therefore, strongly suggests that LRRK2 has minimal role as a candidate and susceptibility gene in PD pathogenesis among East Indians.
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TL;DR: Clinical and genetic information of 5 Japanese patients with Bardet-Biedl syndrome is summarized and it is found that rare liver fibrosis was detected in two patients, while only two patients had renal dysfunction, thought to be a universal symptom.
Abstract: s / Neuroscience Research 68S (2010) e55–e108 e71 of chronic cerebral hypoperfusion. This novel rat model seems to resemble more closely to the condition of human SIVD. doi:10.1016/j.neures.2010.07.077 O1-7-3-4 Japanese patients with Bardet-Biedl syndrome Makito Hirano 1 , Toshihide Yamashita 2, Yasushi Ikuno 3, Hiromi Iwahashi 4, Mitsuru Ohishi 5, Toshiyuki Mano 6, Ryu Ishihara 7, Ichiro Tanaka 8, Keiko Yanagihara 6, Yusaku Nakamura 1, Susumu Kusunoki 9 1 Dept Neurol, Kinki Univ Sakai Hosp, Osaka, Japan 2 Dept Mol Neurosci, Osaka Univ, Osaka, Japan 3 Dept Ophthalmol, Osaka Univ, Osaka, Japan 4 Dept Metab Med, Osaka Univ, Osaka, Japan 5 Dept Geriatr Med, Osaka Univ, Osaka, Japan 6 Div Pediatr Neurol, Osaka Med Center and Res Inst for Mat Child Health, Osaka, Japan 7 Dept Gastrointest Oncol, Osaka Med Center for Cancer and Cardiovas Dis, Osaka Japan 8 Dept Paediatr, Nara Med Univ, Nara, Japan 9 Dept Neurol, Kinki Univ Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mental impairment, rod-cone dystrophy, polydactyly, central obesity, and hypogonadism. The causative genes have been identified as BBS1-14 that encode proteins possibly linked to cilia function, but more than 20% of patients have no mutations found. In the Western countries, this disease is relatively common, however, only a few Japanese patients have been reported in the English-language literature. We summarized clinical and genetic information of 5 Japanese patients with BBS including our patients. DNA array analysis (BBS1-10) was performed in two patients, without identifying any mutations. We found that rare liver fibrosis was detected in two patients, while only two patients had renal dysfunction, thought to be a universal symptom. We speculate that clinical signs and symptoms of patients in Japan may slightly differ from those in other countries. To identify the potential racial difference and the reason for the rarity in Japan, we are currently conducting the nation-wide survey of this disease. doi:10.1016/j.neures.2010.07.078 O1-7-4-1 Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease Wataru Satake 1,2 , Ikuko Mizuta 1, Michiaki Kubo 3, Takahisa Kawaguchi 3, Tatsuhiko Tsunoda 3, Takeo Yoshikawa 4, Saburo Sakoda 2, Mitsutoshi Yamamoto 5, Nobutaka Hattori 6, Miho Murata 7, Yusuke Nakamura 3,8, Tatsushi Toda 1, . Japan PD Gene Consortium 9 1 Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan 2 Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan 3 Center for Genomic Medicine, RIKEN, Yokohama, Japan 4 RIKEN Brain Science Institute, Saitama, Japan 5 Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu, Japan 6 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan 7 Department of Neurology, National Center Hospital of Neurology and Psychiatry, Kodaira, Japan 8 Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan 9 Japan PD Gene Consortium Parkinson’s disease (PD) is a complex disorder caused by multiple genetic and environmental factors. Association studies have evaluated variants in many candidate genes for PD, but only a few genes, such as common variants of ̨synuclein and rare mutations of GBA, have been identified as PD-susceptibility genes with genome-wide significance. To identify further susceptibility variants, 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 = 1.52×10-12) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94×10-9). We also detected strong associations at ̨-synuclein on 4q22 (P = 7.35×10-17) and LRRK2 on 12q12 (P = 2.72×10-8), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals European ancestry, we identified PARK16, ̨-synuclein 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. doi:10.1016/j.neures.2010.07.079 O1-7-4-2 Abnormal autophagy / lysosome function may play some role in Parkinson’s disease Hideaki Matsui 1,3 , Hidefumi Ito 1, Yoshihito Taniguchi 2,3, Shunichi Takeda 2,3, Ryosuke Takahashi 1,3 1 Dept Medicine, Kyoto Univ, Kyoto 2 Dept Radiation Genetics, Kyoto Univ, Kyoto 3 JST, CREST Background: We previously established several kinds of Parkinson model using medaka fish.Objective: To analyze several medaka mutants and toxininduced phenotypes.Methods: We created PINK1 (PARK6), Parkin (PARK2) and ATP13A2 (PARK9) mutant medaka fish. We also exposed ammonium chloride, tunicamycin and lactacystin to medaka fish.Results: PINK1 / Parkin double mutant disclosed selective dopaminergic cell loss, movement disorder. It disckosed impaired autophagy, decreased activity of mitochondria complex I/II and contained lysosome-related abnormal structures in the brain. Similar phenotypes were also demonstrated by mouse embryonic fibloblast. ATP13A2 mutant also disclosed Parkinsonism with similar abnormal structures related with lysosome. Lysosome inhibitor, ammonium chloride, could induce Parkinsonism in medaka fish: Ubiquitin positive inclusion bodies, movement disorder and selective loss of dopaminergic neurons.Conclusions: These lines of evidence suggested that autophagy / lysosome pathway may be a central part of PD mechanism. doi:10.1016/j.neures.2010.07.080 O1-7-4-3 Regulation of the PINK1 signaling by a mitochondrial protein PGAM5 Tomoyo Sawada 1,2 , Tomoko Kanao 3, Yoshito Kobayashi 1, Ryosuke Takahashi 1,2, Yuzuru Imai 3 1 Dept Neurol, Kyoto University, Kyoto 2 JEST-CREST, Tokyo 3 IDAC/CRESS, Tohoku University, Sendai Mutations in PINK1, a nuclear gene encoding a mitochondrial serinethreonine kinase, cause a recessively inherited form of Parkinson,s disease. We biochemically identified PINK1-binding proteins and screened for binding proteins that modulate the Drosophila PINK1 mutant phenotypes. As a result, we identified a member of the phosphoglycerate mutase family PGAM5 as a modulator. Overexpression of PGAM5, which is localized in the outer mitochondrial membrane, resulted in fragmentation of the mitochondria and a shorter lifespan in Drosophila, suggesting that PGAM5 is toxic to cells under a certain condition. We found that loss of a PINK1-binding protein PGAM5 significantly improved degeneration of the indirect flight muscles, motor defect and dopaminergic neurodegeneration caused by PINK1 inactivation. In contrast, removal of the PGAM5 gene failed to rescue the parkin mutant phenotypes. These results suggest that PGAM5 is genetically epistatic to parkin, or independently functions downstream of PINK1 in Drosophila. In this study, we will examine their underlying molecular mechanisms in mammalian cultured cells, focusing on the molecular relationship between PINK1, PGAM5 and Parkin. doi:10.1016/j.neures.2010.07.081 O1-7-4-4 Neuroprotection by type B inhibitors is mediated by type A monoamine oxidase Keiko Inaba-Hasegawa 1 , Makoto Naoi 1, Wakako Maruyama 2, Masayo Shamoto-Nagai 2 1 Gifu International Institute of Biotechnology 2 National Institute for Geriatrics and Gerontology, Japan Inhibitors of type B monoamine oxidase (MAO-B), rasagiline and selegiline, protect neuronal cells against cell death induced by various insults. These protective agents are irreversible MAO-B inhibitors (MAO-B-Is) and bind to the substrate binding site, whereas at quite higher concentrations they bind also to MAO-A at the site besides the substrates binding site. The neuroprotective function of MAO-B-Is is mainly ascribed to the induction of pro-survival genes, bcl-2 and GDNF, BDNF, NGF. The studies on the chemical structure-activity relationship suggest the presence of the binding site in mitochondria, recognizing the stereochemical structures of MAO-B-Is of propargylamine derivatives. In this paper, the role of MAO in the induction
456 citations
TL;DR: The systematic review of the articles reveals that the epidemiology in India may be different with relatively lesser incidence here, and most of the genetic mutations found to cause PD in other population are not found in India, revealing that other genetic factors may be involved.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder affecting patients in large numbers throughout the world. In this article, we review all the published data on PD based on studies in Indian population. We have tried to consolidate the contribution of Indian studies in PD research. We found 95 articles, of which 92 were original research papers. This is a relatively less number, but in the last decade, there has been an increase in research on PD from this country. But most of them seem to be restricted to only a few research institutes. The nonmotor symptoms and genetics are the most commonly studied aspects. The systematic review of the articles reveals that the epidemiology in India may be different with relatively lesser incidence here. Most of the genetic mutations found to cause PD in other population are not found in India, revealing that other genetic factors may be involved. Further research needs to be encouraged to understand the disease in Indian patients better, as all the results cannot be extrapolated from the Western literature to this heterogeneous Indian population. There need to be more studies on therapeutic aspects of the disease.
48 citations
Cites background from "Evaluation of the Role of LRRK2 Gen..."
...[95] In India, none of the patients from four tertiary centers studies had these mutations.[87,96-98] Phosphatase and tensin (PTEN) homolog induced kinase-1 (PINK-1) gene mutations are responsible for PARK-6, comprising 9....
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TL;DR: The results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD, and it is possible that age is not the risk factor to facilitate G23 85R gene mutation.
Abstract: Clinical diagnosis of Parkinson’s disease (PD) is essential but misdiagnosis of PD-like diseases is quite common LRRK2 G2385R variants have been extensively examined for the association to the risk of Parkinson’s disease However, results from different studies are inconsistent The purpose of this meta-analysis was to assess the association between the LRRK2 G2385R variants and the risk of PD A systematic literature search was performed for 6 databases up to January of 2014 to identify case–control studies involving LRRK2 G2385R variants and the risk of PD A total of 12,915 cases and 12,451 controls in 23 case–control studies were included in this meta-analysis The results indicated that the variant A allele carriers (GA + AA) increased risk of PD when compared with the homozygote GG (GA + AA vs GG: OR = 24, 95 % CI = 197 to 292, P < 000001) In the subgroup analysis by ethnicity, increased risks were identified among Chinese (OR = 269, 95 % CI = 21–345, P < 000001) as well as in non-Chinese (OR = 217, 95 % CI 175–269, P < 000001) In the subgroup analysis by age of onset, significant associations were found in both later-onset PD (LOPD) and early-onset PD (EOPD) cases And there was no significant difference of the allele frequency between patients with LOPD and EOPD (OR = 118, 95 % CI = 077–180, P = 045) Our results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD Meanwhile, it is possible that age is not the risk factor to facilitate G2385R gene mutation
20 citations
Cites background from "Evaluation of the Role of LRRK2 Gen..."
...Of these studies, 8 were carried out in China main land [13, 22, 29, 30, 32, 33, 35, 36], 4 on Taiwan [17, 18, 21, 34]; 3 were conducted on Singapore [14, 19, 27] and Japan [20, 24, 26], respectively; 2 on Korean [23, 28], 1 on Thailand [25], East India [31] and Asia [9] with undetermined detailed region, respectively....
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...AA) had a 19 % increased risk of PD in Chinese compared with subjects in NCH (including Japanese, Thai, India, Korea, and East India)....
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TL;DR: The results demonstrate that up to 3.9% (12/308) of PD patients of eastern India harbor DJ-1 variants that should be explored further for any causal relationship with PD.
Abstract: Parkinson’s disease (PD) is a common neurodegenerative movement disorder. Among the candidate genes, DJ-1 accounts for about 1% of the cases in different populations. We aim to find the contribution of the gene towards PD among Indians. By screening DJ-1 in 308 PD patients of eastern India and 248 ethnically matched controls, a total of 21 nucleotide variants – including two nonsynonymous changes – were detected. p.Arg98Gln was identified in 6 unrelated patients and 2 controls while p.Val35Ile, a novel change, was found only in 2 unrelated patients. A SNP (rs7517357) was observed to be moderately associated with increased risk of PD (p 40 years) compared to the controls (> 45 years). Two of the patients, also heterozygotes for PINK1 mutation, had more severe disease phenotypes, consistent with the reported interaction between PINK1 and DJ-1 gene products [19]. Our results demonstrate that up to 3.9% (12/308) of PD patients of eastern India harbor DJ-1 variants that should be explored further for any causal relationship with PD.
18 citations
TL;DR: This study suggests that there is a higher chance to detect associations between PD and those trait-associated SNPs of LRRK2 gene found in Caucasian studies in INS, while those found in Japanese studies are likely to be better replicated among CHB.
Abstract: Genome Wide Association Studies (GWASs) have identified trait-associated polymorphisms via a hypothesis-free approach. However, it is challenging when attempting to reproduce GWAS findings in different populations as it fundamentally relies on the similar patterns of linkage disequilibrium (LD) between the unknown causal variants and the genotyped single nucleotide polymorphisms (SNPs). To address this potential limitation, we examined the regional LD pattern of leucine-rich repeat kinase 2 (LRRK2) gene, which is responsible for both autosomal dominant and sporadic Parkinson’s disease (PD), in Caucasians (CEU), Japanese (JPT) and Chinese (CHB) from HapMap and Chinese (CHS), Malays (MAS) and Indians (INS) from the Singapore Genome Variation Project (SGVP) utilizing the traditional heatmaps and targeted analysis of LRRK2 gene via Monte Carlo simulation through varLD scores of these ethnic groups. Both heatmaps and targeted analysis showed that LD pattern of JPT was different from that of INS (P=0.0001); while LD pattern of CEU was different from that in Asian except for INS (all P=0.0001). Our study suggests that there is a higher chance to detect associations between PD and those trait-associated SNPs of LRRK2 gene found in Caucasian studies in INS, while those found in Japanese studies are likely to be better replicated among CHB.
16 citations
Cites background from "Evaluation of the Role of LRRK2 Gen..."
...A common recurrent mutation G2019S has an average worldwide frequency of 1% in sporadic PD patients [4] and 2%–7% in Caucasian familial cases [8–11], and up to 20% in Ashkenazi Jews [12] and 40% in North African Arabs [13], but not in East Indians [7]....
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...mutations in LRRK2 is a rare cause of PD in East Indians [7]....
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...Mutations in LRRK2 gene represent the most common causes of autosomal dominant inherited and sporadic PD worldwide [3–6], however, mutations in LRRK2 is a rare cause of PD in East Indians [7]....
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References
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TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Availability: http://www.broad.mit.edu/mpg/haploview/
Contact: jcbarret@broad.mit.edu
13,862 citations
"Evaluation of the Role of LRRK2 Gen..." refers methods in this paper
...1 was used to test the LD block and predict the haplotypes for the SNPs [1]....
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National Institutes of Health1, University of Tübingen2, University of Coimbra3, University College London4, University of Luxembourg5, University of Lübeck6, Washington University in St. Louis7, University of Bonn8, University of Florida9, University of Kiel10, Baylor College of Medicine11, Scripps Research Institute12, AARP13, Penn State Milton S. Hershey Medical Center14
TL;DR: It is demonstrated that an unequivocal role for common genetic variants in the etiology of typical PD and population-specific genetic heterogeneity in this disease is suggested, and supporting evidence that common variation around LRRK2 modulates risk for PD is provided.
Abstract: We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
1,793 citations
TL;DR: The 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.
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.
1,206 citations
Journal Article•
TL;DR: The results of seven population-based studies were examined separately and pooled to obtain age- and sex-specific estimates of the prevalence of PD and found no sex differences in prevalence.
Abstract: Data are lacking on the prognosis (institutionalization and death) of PD cases identified in population-based studies. Data from five population-based European studies were compared and pooled. Each study used comparable two-step screening methods to identify cases and performed one or more follow-up examinations of their respective participants after defined periods of time. PD was classified on the basis of questionnaire and clinical data. The studies include 16,143 participants (252 with PD). The relative risk (RR) (95% CI) of death associated with PD was 2.3 (1.8 to 3.0). The risk for death in men with PD (RR 3.1 [2.1 to 4.4]) was higher than in women with PD (RR 1. 8 [1.2 to 5.1]). The rate of institutionalization varied across studies, increased with age, and was considerably higher in PD cases compared to noncases. Women with PD had a fivefold higher risk to live in a care facility than did men with PD. These data on mortality and rate of institutionalization reflect the high burden of PD in the population.
773 citations
TL;DR: It is shown that a common single Mendelian mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinson's disease, and suggested that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's Disease.
Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinson's disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinson's disease. We assessed 482 patients with the disorder, of whom 263 had pathologically confirmed disease, by direct sequencing for mutations in exon 41 of LRRK2. The mutation was present in eight (1.6%) patients. We have shown that a common single Mendelian mutation is implicated in sporadic Parkinson's disease. We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's disease.
735 citations