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ABSTRACT: Age at onset serves as a predictor of progression and mortality in sporadic Parkinson's disease (PD). Therefore, the identification of genetic modifiers for age at onset might lead to a better understanding of disease pathogenesis. We performed multivariate linear regression analysis in 1396 sporadic PD patients assessing 21 single-nucleotide polymorphisms (SNPs) that have been previously suggested to be associated with sporadic PD. Moreover, a cumulative risk score was assigned to each patient and correlated with age at onset. We identified the rs356219 risk allele in the SNCA gene as significantly contributing to earlier age at onset. Neither one of the other 21 SNPs tested in this analysis nor the cumulative number of risk alleles showed a significant impact on PD onset. Because sequence variants in the SNCA gene are not only associated with autosomal dominantly inherited PD and increased susceptibility for sporadic PD but also have been found to modify the phenotype such as age at onset in both sporadic and various monogenic forms of PD, this gene serves as an outstanding target for further research on PD pathogenesis, which in return might provide potential therapeutic options. © 2013 Movement Disorder Society.
Movement Disorders 05/2013; · 4.51 Impact Factor
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Michael A Nalls,
Raquel Duran,
Grisel Lopez,
Marzena Kurzawa-Akanbi,
Ian G McKeith,
Patrick F Chinnery,
Christopher M Morris,
Jessie Theuns,
David Crosiers,
Patrick Cras, [......],
Benoit I Giasson,
John Q Trojanowski,
Howard I Hurtig,
Nahid Tayebi,
Claudia Landazabal,
Melanie A Knight,
Margaux Keller,
Andrew B Singleton,
Tyra G Wolfsberg,
Ellen Sidransky
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ABSTRACT: IMPORTANCE While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING Eleven centers from sites around the world performing genotyping. PARTICIPANTS Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
JAMA neurology. 04/2013;
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Daniela Berg,
Anthony E Lang,
Ronald B Postuma,
Walter Maetzler,
Guenther Deuschl, Thomas Gasser,
Andrew Siderowf,
Anthony H Schapira,
Wolfgang Oertel,
José A Obeso,
C Warren Olanow,
Werner Poewe,
Matthew Stern
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ABSTRACT: Recent findings question our present understanding of Parkinson's disease and suggest that new research criteria for the diagnosis of Parkinson's disease are needed, similar to those recently defined in Alzheimer's disease. However, our ability to redefine Parkinson's disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinson's disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinson's disease but without Lewy pathology. Although it is too early to confidently redefine Parkinson's disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinson's disease.
The Lancet Neurology 04/2013; · 23.46 Impact Factor
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Stephan Klebe,
Jean-Louis Golmard,
Michael A Nalls,
Mohamad Saad,
Andrew B Singleton,
Jose M Bras,
John Hardy,
Javier Simon-Sanchez,
Peter Heutink,
Gregor Kuhlenbäumer, [......],
Philippe Amouyel,
Jean-Charles Lambert,
Christophe Tzourio,
Cécilia Maubaret,
Fanny Charbonnier-Beaupel,
Khadija Tahiri,
Marie Vidailhet,
Maria Martinez,
Alexis Brice,
Jean-Christophe Corvol
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ABSTRACT: The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
Journal of neurology, neurosurgery, and psychiatry 02/2013; · 4.87 Impact Factor
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Silke Appenzeller,
Claudia Schulte,
Sandra Thier,
Franziska Hopfner,
Manuela Pendziwiat,
Frank Papengut,
Christine Klein,
Johann Hagenah,
Meike Kasten,
Karin Srulijes,
Daniela Berg, Thomas Gasser,
Andrew Singleton,
Günther Deuschl,
Gregor Kuhlenbäumer
Movement Disorders 02/2013; · 4.51 Impact Factor
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Gregor K Wenning,
Felix Geser,
Florian Krismer,
Klaus Seppi,
Susanne Duerr,
Sylvia Boesch,
Martin Köllensperger,
Georg Goebel,
Karl P Pfeiffer,
Paolo Barone, [......],
Ruth Djaldetti,
Eldad Melamed, Thomas Gasser,
Christoph Kamm,
Giuseppe Meco,
Carlo Colosimo,
Olivier Rascol,
Wassilios G Meissner,
François Tison,
Werner Poewe
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ABSTRACT: BACKGROUND: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. METHODS: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. FINDINGS: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. INTERPRETATION: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. FUNDING: Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.
The Lancet Neurology 02/2013; · 23.46 Impact Factor
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ABSTRACT: Disturbances of smell and taste are common. About 5% of the general population have anosmia (absence of the sense of smell). Olfactory dysfunction can markedly impair the quality of life.
Review of pertinent literature retrieved by a selective search.
In recent years, simple and reliable tests of the sense of smell have been introduced in otorhinolaryngology. Olfactory testing has become a new focus of attention in neurology as well, mainly because many patients with neurodegenerative diseases-including the majority of those with Parkinson's or Alzheimer's disease-have olfactory loss early on in the course of their disorder. Olfactory dysfunction is thus regarded as an early sign of neurodegenerative disease that may allow a tentative diagnosis to be made years before the motor or cognitive disturbances become evident. As for the treatment of olfactory loss, anti-inflammatory drugs and surgery can help in some cases, and olfactory training can lead to significant improvement of post-viral olfactory deficits.
Olfactory dysfunction is common and becomes more common with advancing age. It is increasingly receiving attention as an important sign for the early diagnosis and the differential diagnosis of neurodegenerative disorders.
01/2013; 110(1-2):1-7. · 2.92 Impact Factor
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ABSTRACT: BACKGROUND AND OBJECTIVE: Preclinical studies suggest an increased vaporization rate and speed of the 532 nm 180-W XPS GreenLight laser (180-W) compared with the 120-W HPS GreenLight laser (120-W) and the 80-W PV GreenLight laser (80-W). To test the clinical relevance of this observation we analyzed intraoperative data and early postoperative results after photoselective vaporization of the prostate (PVP) with the 180-W, 120-W, and 80-W laser. STUDY DESIGN/MATERIALS AND METHODS: A retrospective pair-to-pair comparison was performed including 80 consecutive patients who underwent PVP for the treatment of benign prostate enlargement with the 180-W, 120-W, and 80-W laser. The groups matched concerning age, prostate volume, PSA-value, and preoperative catheterization. Primary study outcome measurement was PSA-value reduction at 3 months; intraoperative data, perioperative complications, and early postoperative functional course were secondary study outcome measurements. RESULTS: Energy application per case (kJ), preoperative prostate volume (kJ/ml) operating time (kJ/minute), and lasing time (kJ/minute) was significantly higher with the 180-W laser. Prevalence of impaired visibility due to bleeding was comparable between the 180-W and the 120-W laser but significantly lower with 80-W. Duration of hospitalization was shorter with the 180-W laser compared to the former laser systems. During the postoperative course of 3 months voiding parameters and micturition symptoms significantly improved in all groups, the incidence of postoperative dysuria was comparable. Postoperative PSA-value reduction was significantly higher after treatment with the 180-W laser. CONCLUSIONS: With the 180-W laser, higher energy application and higher speed of tissue vaporization leads to increased tissue vaporization compared to the former 120-W and 80-W laser systems. Clinical efficacy and perioperative safety are maintained with the higher powered laser. Lasers Surg. Med. © 2012 Wiley Periodicals, Inc.
Lasers in Surgery and Medicine 12/2012; · 2.75 Impact Factor
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Peter Holmans,
Valentina Moskvina,
Lesley Jones,
Manu Sharma,
Finja Buchel,
Mohamad Sadd,
Jose M Bras,
Francesco Bettella,
Nayia Nicolaou,
Javier Simón-Sánchez, [......],
Kari Majamaa, Thomas Gasser,
Peter Heutink,
Nicholas W Wood,
Maria Martinez,
Andrew B Singleton,
Michael A Nalls,
John Hardy,
Huw R Morris,
Nigel M Williams
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ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people over 60 and 3-4% in people over 80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (p<1x10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD we applied a pathway based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD associated genes (minimum p=0.014 and p=0.006 respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (p<0.001) implicating genes involved in the regulation of leukocyte/lymphocyte activity and also cytokine mediated signalling as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings therefore provide independent support to the strong association signal at the HLA locus and imply that the immune related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
Human Molecular Genetics 12/2012; · 7.64 Impact Factor
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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
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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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ABSTRACT: BACKGROUND: A locus implicated in autosomal dominant cervical dystonia was assigned to chromosome 18p in 1 large family more than 15 years ago. This locus was designated DYT7. We reanalyzed the family clinically and genetically. METHODS: Clinical reevaluation of all family members was performed. There was Sanger sequencing of candidate genes, SNP array analysis, and exome sequencing in definitely affected family members. RESULTS: Diagnosis of cervical dystonia was definite in 6 family members and possible in 12. Analysis of candidate genes in 18p revealed no alteration in definitely affected patients. There was no disease causing copy number variant in 18p. No potentially disease-causing mutations were detected in 18p by exome sequencing. The CIZ1 gene, mutated in some cases of cervical dystonia, was excluded. CONCLUSIONS: Location of DYT7 on 18p in autosomal dominant cervical dystonia is questionable. We demonstrate genetic heterogeneity of this form of dystonia. © 2012 Movement Disorder Society.
Movement Disorders 10/2012; · 4.51 Impact Factor
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Daniela Berg,
Stefanie Behnke,
Klaus Seppi,
Jana Godau,
Stefanie Lerche,
Philipp Mahlknecht,
Inga Liepelt-Scarfone,
Christoph Pausch,
Niko Schneider,
Alexandra Gaenslen, [......],
Karin Srulijes,
Heiko Huber,
Isabel Wurster,
Heike Stockner,
Stefan Kiechl,
Johann Willeit,
Arno Gasperi,
Klaus Fassbender, Thomas Gasser,
Werner Poewe
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ABSTRACT: BACKGROUND: SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinson's disease (PD). Recently, we reported a 17.4-fold increased risk for PD in individuals with SN+ older than 50 years within 3 years. METHODS: This is the second follow-up of a prospective, longitudinal, three-center observational study after 5 years. Of the initial 1,847 at baseline PD-free participants 50 years or older, 1,271 underwent the 5-year reassessment. RESULTS: Within 5 years, 21 individuals developed incident PD. Participants with SN+ at baseline had a more than 20.6 times increased risk to develop PD in this time span than those without this echo feature. CONCLUSION: We thus confirm our finding of the 3-year follow-up examination in a longer observation time and higher number of individuals with incident PD and suggest SN+ as an important risk marker for PD. © 2012 Movement Disorder Society.
Movement Disorders 10/2012; · 4.51 Impact Factor
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Carola Seifried,
Sandra Boehncke,
Jannika Heinzmann,
Simon Baudrexel,
Lutz Weise, Thomas Gasser,
Karla Eggert,
Wolfgang Fogel,
Horst Baas,
Klaus Badenhoop,
Helmuth Steinmetz,
Rüdiger Hilker
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ABSTRACT: Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life in patients with advanced Parkinson´s disease (PD), but is associated with neuropsychiatric side effects and weight gain in some individuals. The pathomechanisms of these phenomena are still unknown. Considering anatomical and functional connections of the STN with the hypothalamic-pituitary (HP) system, we prospectively investigated whether chronic STN-DBS alters HP functioning in 11 PD patients. Methods: Basal hormone levels of the HP-adrenal (HPA), -gonadal and -somatotropic axis were determined before surgery as well as 3 and 6 months after electrode implantation. In addition, 24-hour cortisol profiles and dexamethasone suppression tests were obtained. Postoperative hormone changes were correlated with individual neuropsychological test performance, psychiatric status and anthropometric measures. Results: While PD patients experienced weight gain (p = 0.025) at follow-up, most neuropsychological data and basal HP hormone levels did not change over time. HPA regulation and diurnal rhythmicity of cortisol remained intact in all patients. The 24-hour mean cortisol levels decreased 6 months after surgery (p = 0.002) correlating with improved postoperative depression (p = 0.02). Conclusions: Chronic application of high-frequent electrical stimuli in the STN was not associated with HP dysfunction in patients with advanced PD. The diurnal variability of peripheral cortisol secretion as one important element of the endogenous biological clock remained intact. Evening cortisol levels decreased after surgery reflecting a favourable regulation of the cortisol setpoint. STN-DBS can be considered safe from a neuroendocrine perspective, but the origin of unwanted side effects warrants further elucidation.
Neuroendocrinology 10/2012; · 2.38 Impact Factor
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Margaux F Keller,
Mohamad Saad,
Jose Bras,
Francesco Bettella,
Nayia Nicolaou,
Javier Simón-Sánchez,
Florian Mittag,
Finja Büchel,
Manu Sharma,
J Raphael Gibbs, [......],
Kari Majamaa,
Huw R Morris,
Nigel Williams, Thomas Gasser,
Peter Heutink,
Nicholas W Wood,
John Hardy,
Maria Martinez,
Andrew B Singleton,
Michael A Nalls
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ABSTRACT: Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
Human Molecular Genetics 08/2012; 21(22):4996-5009. · 7.64 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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Silke Appenzeller,
Sandra Thier,
Frank Papengut,
Christine Klein,
Johann Hagenah,
Meike Kasten,
Daniela Berg,
Karin Srulijes, Thomas Gasser,
Stefan Schreiber,
Günther Deuschl,
Gregor Kuhlenbäumer
Movement Disorders 07/2012; 27(9):1191-2. · 4.51 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
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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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Florian Mittag,
Finja Büchel,
Mohamad Saad,
Andreas Jahn,
Claudia Schulte,
Zoltan Bochdanovits,
Javier Simón-Sánchez,
Mike A Nalls,
Margaux Keller,
Dena G Hernandez, [......],
Suzanne Lesage,
Alexis Brice,
Peter Heutink,
Maria Martinez,
Nicholas W Wood,
John Hardy,
Andrew B Singleton,
Andreas Zell, Thomas Gasser,
Manu Sharma
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ABSTRACT: The success of genome-wide association studies (GWAS) in deciphering the genetic architecture of complex diseases has fueled the expectations whether the individual risk can also be quantified based on the genetic architecture. So far, disease risk prediction based on top-validated single-nucleotide polymorphisms (SNPs) showed little predictive value. Here, we applied a support vector machine (SVM) to Parkinson disease (PD) and type 1 diabetes (T1D), to show that apart from magnitude of effect size of risk variants, heritability of the disease also plays an important role in disease risk prediction. Furthermore, we performed a simulation study to show the role of uncommon (frequency 1-5%) as well as rare variants (frequency <1%) in disease etiology of complex diseases. Using a cross-validation model, we were able to achieve predictions with an area under the receiver operating characteristic curve (AUC) of ∼0.88 for T1D, highlighting the strong heritable component (∼90%). This is in contrast to PD, where we were unable to achieve a satisfactory prediction (AUC ∼0.56; heritability ∼38%). Our simulations showed that simultaneous inclusion of uncommon and rare variants in GWAS would eventually lead to feasible disease risk prediction for complex diseases such as PD. The used software is available at http://www.ra.cs.uni-tuebingen.de/software/MACLEAPS/.
Human Mutation 07/2012; · 5.69 Impact Factor
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Sandra Thier,
Delia Lorenz,
Michael Nothnagel,
Caroline Poremba,
Frank Papengut,
Silke Appenzeller,
Steffen Paschen,
Frank Hofschulte,
Anna-Christina Hussl,
Sascha Hering,
Werner Poewe,
Friedrich Asmus, Thomas Gasser,
Ludger Schöls,
Kaare Christensen,
Almut Nebel,
Stefan Schreiber,
Stephan Klebe,
Günther Deuschl,
Gregor Kuhlenbäumer
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ABSTRACT: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET.
Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET.
We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10(-10), OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087.
We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.
Neurology 07/2012; 79(3):243-8. · 8.31 Impact Factor
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Kathrin Brockmann,
Ruediger Hilker,
Ulrich Pilatus,
Simon Baudrexel,
Karin Srulijes,
Jörg Magerkurth,
Ann-Kathrin Hauser,
Claudia Schulte,
Ilona Csoti,
Caroline Denise Merten, Thomas Gasser,
Daniela Berg,
Elke Hattingen
[show abstract]
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ABSTRACT: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)-associated Parkinson disease (PD) using combined proton ((1)H) and phosphorus ((31)P) magnetic resonance spectroscopic imaging (MRSI) in vivo.
(1)H and (1)H-decoupled (31)P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified.
Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from (1)H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest.
The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.
Neurology 06/2012; 79(3):213-20. · 8.31 Impact Factor
