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1.
Biskup S Mueller JC Sharma M Lichtner P Zimprich A Berg D Wüllner U Illig T Meitinger T Gasser T 《Annals of neurology》2005,58(6):905-908
Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk. 相似文献
2.
G. Xiromerisiou G. M. Hadjigeorgiou V. Gourbali J. Johnson I. Papakonstantinou A. Papadimitriou A. B. Singleton 《European journal of neurology》2007,14(1):7-11
Mutations in SNCA and LRRK2 genes, encoding alpha-synuclein and leucine-rich repeat kinase 2, respectively, cause autosomal dominant Parkinson's disease (AdPD). The LRRK2 G2019S (c.6055G > A) and R1441G (c.4321C > G) mutations have also been identified in sporadic PD (sPD). We studied 55 unrelated patients with AdPD, 235 patients with sPD, and 235 healthy age- and gender-matched controls all of Greek origin. Patients with AdPD were screened for SNCA and LRRK2 mutations by direct sequencing. SNCA gene dosage analysis was also performed for AdPD using quantitative duplex polymerase chain reaction of genomic DNA. In addition, we investigated the frequency of the LRRK2 G2019S mutation in sPD. We found no missense mutations or multiplications in the SNCA gene. Here we report two novel variants, A211V (c.632C > T) and K544E (c.1630A > G) in LRRK2 gene in two patients with AdPD that was not present in controls. We identified only one patient with sPD (1/235; 0.4%) carrying the G2019S mutation. LRRK2 mutations are present in AdPD and sPD patients of Greek origin. 相似文献
3.
Lack of G2019S LRRK2 mutation in a cohort of Taiwanese with sporadic Parkinson's disease. 总被引:3,自引:0,他引:3
Hon-Chung Fung Chiung-Mei Chen John Hardy Dena Hernandez Andrew Singleton Yih-Ru Wu 《Movement disorders》2006,21(6):880-881
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant and sporadic Parkinson's disease (PD). We report here the frequency of a common heterozygous mutation, 2877510G>A, which produces a glycine-to-serine amino acid substitution at codon 2019 in idiopathic Taiwanese PD. The extreme rarity of the G2019S mutation in our population suggests the occurrence of this mutation resulted from a common European founder. 相似文献
4.
Ross OA Soto-Ortolaza AI Heckman MG Aasly JO Abahuni N Annesi G Bacon JA Bardien S Bozi M Brice A Brighina L Van Broeckhoven C Carr J Chartier-Harlin MC Dardiotis E Dickson DW Diehl NN Elbaz A Ferrarese C Ferraris A Fiske B Gibson JM Gibson R Hadjigeorgiou GM Hattori N Ioannidis JP Jasinska-Myga B Jeon BS Kim YJ Klein C Kruger R Kyratzi E Lesage S Lin CH Lynch T Maraganore DM Mellick GD Mutez E Nilsson C Opala G Park SS Puschmann A Quattrone A Sharma M Silburn PA Sohn YH Stefanis L Tadic V 《Lancet neurology》2011,10(10):898-908
Background
Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.Methods
LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab–Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.Findings
121 exonic LRRK2 variants were assessed in 15?540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab–Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15–1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35–3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab–Berber series (combined odds ratio 0·82, 0·72–0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20–2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36–1·07; p=0·087). In the Arab–Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33–15·09; p=0·012).Interpretation
The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.Funding
Michael J Fox Foundation and National Institutes of Health. 相似文献5.
6.
Lavinia Athanasiu Morten Mattingsdal Anna K. Kähler Andrew Brown Omar Gustafsson Ina Giegling Sven Cichon Marcella Rietschel Leena Peltonen Elvira Bramon David St. Clair Hannes Petursson Ingrid Melle Vidar M. Steen Srdjan Djurovic Ole A. Andreassen 《Journal of psychiatric research》2010,44(12):748-219
We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P < 8.7 × 10−8). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value < 0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities. 相似文献
7.
8.
The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease 总被引:3,自引:0,他引:3
Lu CS Simons EJ Wu-Chou YH Fonzo AD Chang HC Chen RS Weng YH Rohé CF Breedveld GJ Hattori N Gasser T Oostra BA Bonifati V 《Parkinsonism & related disorders》2005,11(8):521-522
9.
目的探讨GRIN2B和SNCA基因多态性与不伴痴呆的帕金森病(PD)患者的幻觉症状是否相关。方法利用SNa Pshot SNP分型技术检测2个基因多态性,对53例幻觉组和47例无幻觉组及其两个亚组之间进行相关性分析。结果 GRIN2B和SNCA在PD有幻觉组和PD无幻觉组及其两个亚组的等位基因和基因型频率不存在显著差异。校正临床相关因素后,GRIN2B rs7301328的GG基因型降低PD相关幻觉发生风险(Recessive:OR’=0.246,95%CI[0.071~0.848],P’=0.026;Additive:OR’=0.432,95%CI[0.208~0.895],P’=0.024)。SNCA rs894278的GG基因型增加早发型PD幻觉发生的风险(Recessive:OR’=8.281,95%CI[1.217~56.334],P’=0.031)。未发现与PD幻觉迟发型的幻觉风险增加相关的基因多态性。结论在中国人不伴痴呆的PD人群中,GRIN2B rs7301328的GG基因型可能是PD相关幻觉的保护因素。而SNCA rs894278的GG基因型可能是PD患者幻觉早发型的幻觉发生的危险因素。 相似文献
10.
Li HL Shi SS Guo QH Ni W Dong Y Liu Y Sun YM Bei-Wang Lu SJ Hong Z Wu ZY 《Journal of Alzheimer's disease : JAD》2011,25(1):111-117
Alzheimer's disease (AD) is the most common form of senile dementia, and the overall prevalence increases exponentially with age. It is well known that genetic variants may play an important role in the pathogenesis of this disorder. Recently, two independent large-scale genome-wide association studies (GWAS) identified 3 novel single nucleotide polymorphisms (SNPs) (rs11136000 within CLU, rs3851179 within PICALM and rs6656401 within CR1) that are associated with late-onset AD (LOAD), and these results have been replicated by other studies performed in the Caucasian population. Recently, an independent study failed to verify the association for the SNP within CLU in a Han Chinese population, indicating that there may be genetic heterogeneity in this association. In the present study, we studied the SNPs within PICALM and CR1 in 474 sporadic AD patients (SAD) and 591 unrelated age- and sex-matched healthy controls of Han Chinese descent. Our data revealed that the frequencies of both of these SNPs were not significantly difference between the SAD and control groups. Thus, the association between SNPs within PICALM, CR1, and SAD should be studied further in different ethnic groups. 相似文献
11.
Gaël Nicolas Rocío Acuña-Hidalgo Michael J. Keogh Olivier Quenez Marloes Steehouwer Stefan Lelieveld Stéphane Rousseau Anne-Claire Richard Manon S. Oud Florent Marguet Annie Laquerrière Chris M. Morris Johannes Attems Colin Smith Olaf Ansorge Safa Al Sarraj Thierry Frebourg Dominique Campion Alexander Hoischen 《Alzheimer's & dementia》2018,14(12):1632-1639
Introduction
A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes.Methods
We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years).Results
We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon-based deep sequencing.Discussion
Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases. 相似文献12.
13.
We here summarize the results of genetic investigations on a series of 82 parkinsonian patients from 60 families in Taiwan. We found 13 parkin patients in 7 families (12%), 2 PINK1 sibs from 1 family, and 1 LRRK2 patient from 1 family with I2012T mutation. We also identified SCA2 in 8 patients from 5 families (8%) and SCA3 in 3 patients from 1 family, all presenting with parkinsonian phenotype. In the available patients with parkin, PINK1, SCA2 and SCA3, the dopamine transporter (DAT) scan revealed that the reduction of uptake was primarily observed in the bilateral putamen, basically sharing a similar pattern with that in idiopathic Parkinson's disease. We concluded that the genetic causes contributed to about 25% of our series of familial parkinsonism. The parkin mutations and SCA2 were the most frequent genetic causes in our series with Chinese ethnicity. The results of DAT scan indicated that bilateral putamen was essentially involved in various genetically-caused familial parkinsonism. 相似文献
14.
LRRK2 mutations in a clinic-based cohort of Parkinson's disease 总被引:1,自引:0,他引:1
S. Scholz R. J. Mandel H. H. Fernandez K. D. Foote R. L. Rodriguez E. Barton S. Munson A. Singleton M. S. Okun 《European journal of neurology》2006,13(12):1298-1301
In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2 , encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD. 相似文献
15.
Thanh GN Ton Mary Anne Rossing Deborah J Bowen Sengkeo Srinouanprachan Kristine Wicklund Federico M Farin 《Behavioral and brain functions : BBF》2007,3(1):22-10
Background
Genes involved in dopaminergic neurotransmission have been suggested as candidates for involvement in smoking behavior. We hypothesized that alleles associated with reduced dopaminergic neurotransmission would be more common in continuing smokers than among women who quit smoking. 相似文献16.
Riccardo Zuliani T. William J. MoorheadMark E. Bastin Eve C. JohnstoneStephen M. Lawrie Paolo Brambilla Michael C. O'DonovanMichael J. Owen Jeremy HallAndrew M. McIntosh 《Psychiatry Research: Neuroimaging》2011,191(2):133-137
Variations in the signalling NRG1-ErbB4 pathway have been associated with genetic susceptibility for both bipolar disorder and schizophrenia, although the underlying neural mechanisms are still uncertain. Reduced integrity of the anterior limb of the internal capsule (ALIC) has been found in association with risk-associated genetic variation in the 5′ region of the NRG1 gene. We hypothesised that variation in the gene encoding the NRG1 receptor, ErbB4, would also be associated with reduced ALIC integrity and with cognitive impairments characteristic of individuals with bipolar disorder and schizophrenia. Using diffusion tensor imaging (DTI), we examined the white matter integrity associations of the ErbB4 polymorphism rs4673628, which resides within intron 12 of the gene encoding ErbB4, in 36 healthy individuals. We also sought to clarify the cognitive effects of any findings. We found that genetic variation at the rs4673628 locus in the ErbB4 gene was significantly associated with ALIC white matter integrity which was also significantly and positively associated with mnemonic function. These findings provide further evidence to support a key role of NRG1-ErbB4 signalling in the pathophysiology of major mental disorders. 相似文献
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18.
There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome beta4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups. 相似文献
19.
《Journal of stroke and cerebrovascular diseases》2023,32(4):106998
PurposeLet-7 family members serve as crucial regulatory molecules in the pathogenesis of ischemic stroke. We predicted that genetic variations in the let-7 family's promoters may be linked to the risk of ischemic stroke. The connection of rs10877887 and rs13293512 in the let-7 family promoters with liability to ischemic stroke was explored in this study.Patients and methodsClinical data and peripheral blood samples were collected from 914 ischemic stroke patients and 836 controls in this case–control study. All statistical analyses were carried out using SPSS.ResultsOur analysis results reveal that the rs10877887 TC+CC genotype in the dominant model is associated with a lower risk of ischemic stroke than the TT genotype. Individuals with heterozygous TC or homozygous CC genotypes in the male population showed higher odds of ischemic stroke than those with the wild TT genotype in rs13293512 analysis. Furthermore, there existed a multiplicative interaction between the rs10877887 C allele and the rs13293512 T allele. In the presence of the rs13293512 T allele, the effect of the rs10877887 C allele on ischemic stroke risk was increased. Similarly, in the presence of the rs10877887 C allele, the outcome of the rs13293512 T allele on ischemic stroke risk was elevated. In addition, the rs13293512 CC genotype seemed to lead to an earlier onset of ischemic stroke.ConclusionOur findings indicated that these two SNPs might have a joint role in IS and could potentially act as risk markers. Detecting let-7 promoter polymorphisms could raise awareness of the risk of IS, which directed individuals with risk alleles to have regular checks at an appropriate frequency to avoid developing the disease. 相似文献
20.
Alexander Jung Andreas Huge Gregor Kuhlenbäumer Steffi Kempt Tanja Seehafer Stefan Evers Klaus Berger Martin Marziniak 《Journal of neural transmission (Vienna, Austria : 1996)》2010,117(11):1253-1260
The serotonergic system plays a major role in the etiology of migraine. The rate-limiting enzyme in serotonin homeostasis
and availability is tryptophan hydroxylase (TPH). The TPH2 isoform is responsible for the cerebral serotonin biosynthesis.
To investigate the role of genetic variation in TPH2 in the pathogenesis of migraine eight haplotype tagging SNPs covering the whole TPH2 gene where chosen using Haploview and genotyped in 503 migraineurs and 515 healthy controls. Association analysis was performed
on a single SNP and haplotype basis using χ
2 and logistic regression analysis. Single SNP analysis revealed a weak association with migraine, which did not remain after
correction for multiple testing. Haplotype analyses revealed association of a haplotype with migraine without aura. Stratification
by aura and triptan response did not reveal a positive association with the investigated polymorphisms. These results suggest
a possible influence of genetic variation in TPH2 in the pathogenesis of migraine. 相似文献