Publications

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Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

Neurology 2015-10-13 85(15):1283-92

Wang L,Aasly JO,Annesi G,Bardien S,Bozi M,Brice A,Carr J,Chung SJ,Clarke C,Crosiers D,Deutschländer A,Eckstein G,Farrer MJ,Goldwurm S,Garraux G,Hadjigeorgiou GM,Hicks AA,Hattori N,Klein C,Jeon B,Kim YJ,Lesage S,Lin JJ,Lynch T,Lichtner P,Lang AE,Mok V,Jasinska-Myga B,Mellick GD,Morrison KE,Opala G,Pihlstrøm L,Pramstaller PP,Park SS,Quattrone A,Rogaeva E,Ross OA,Stefanis L,Stockton JD,Silburn PA,Theuns J,Tan EK,Tomiyama H,Toft M,Van Broeckhoven C,Uitti RJ,Wirdefeldt K,Wszolek Z,Xiromerisiou G,Yueh KC,Zhao Y,Gasser T,Maraganore DM,Krüger R,Sharma M,GEO-PD Consortium

Abstract

We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.
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Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease.

Neurology 2014-11-18 83(21):1906-13

Theuns J,Verstraeten A,Sleegers K,Wauters E,Gijselinck I,Smolders S,Crosiers D,Corsmit E,Elinck E,Sharma M,Krüger R,Lesage S,Brice A,Chung SJ,Kim MJ,Kim YJ,Ross OA,Wszolek ZK,Rogaeva E,Xi Z,Lang AE,Klein C,Weissbach A,Mellick GD,Silburn PA,Hadjigeorgiou GM,Dardiotis E,Hattori N,Ogaki K,Tan EK,Zhao Y,Aasly J,Valente EM,Petrucci S,Annesi G,Quattrone A,Ferrarese C,Brighina L,Deutschländer A,Puschmann A,Nilsson C,Garraux G,LeDoux MS,Pfeiffer RF,Boczarska-Jedynak M,Opala G,Maraganore DM,Engelborghs S,De Deyn PP,Cras P,Cruts M,Van Broeckhoven C,GEO-PD Consortium

Abstract

The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort. C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low. Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.
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Alpha-synuclein repeat variants and survival in Parkinson's disease.

Movement disorders : official journal of the Movement Disorder Society 2014-07-22 29(8):1053-7

Chung SJ,Biernacka JM,Armasu SM,Anderson K,Frigerio R,Aasly JO,Annesi G,Bentivoglio AR,Brighina L,Chartier-Harlin MC,Goldwurm S,Hadjigeorgiou G,Jasinska-Myga B,Jeon BS,Kim YJ,Krüger R,Lesage S,Markopoulou K,Mellick G,Morrison KE,Puschmann A,Tan EK,Crosiers D,Theuns J,Van Broeckhoven C,Wirdefeldt K,Wszolek ZK,Elbaz A,Maraganore DM,Genetic Epidemiology of Parkinson's Disease Consortium

Abstract

To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. Twenty-one sites contributed data for 6,154 cases. There was no significant association between α-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). In our large consortium study, α-synuclein REP1 genotypes were not associated with survival in PD. Further studies of α-synuclein's role in disease progression and long-term outcomes are needed.
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Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.

Neurobiology of aging 2014-01-22 35(1):266.e5-14

Heckman MG,Elbaz A,Soto-Ortolaza AI,Serie DJ,Aasly JO,Annesi G,Auburger G,Bacon JA,Boczarska-Jedynak M,Bozi M,Brighina L,Chartier-Harlin MC,Dardiotis E,Destée A,Ferrarese C,Ferraris A,Fiske B,Gispert S,Hadjigeorgiou GM,Hattori N,Ioannidis JP,Jasinska-Myga B,Jeon BS,Kim YJ,Klein C,Kruger R,Kyratzi E,Lin CH,Lohmann K,Loriot MA,Lynch T,Mellick GD,Mutez E,Opala G,Park SS,Petrucci S,Quattrone A,Sharma M,Silburn PA,Sohn YH,Stefanis L,Tadic V,Tomiyama H,Uitti RJ,Valente EM,Vassilatis DK,Vilariño-Güell C,White LR,Wirdefeldt K,Wszolek ZK,Wu RM,Xiromerisiou G,Maraganore DM,Farrer MJ,Ross OA,Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium

Abstract

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
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Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Movement disorders : official journal of the Movement Disorder Society 2013-10-22 28(12):1740-4

Heckman MG,Soto-Ortolaza AI,Aasly JO,Abahuni N,Annesi G,Bacon JA,Bardien S,Bozi M,Brice A,Brighina L,Carr J,Chartier-Harlin MC,Dardiotis E,Dickson DW,Diehl NN,Elbaz A,Ferrarese C,Fiske B,Gibson JM,Gibson R,Hadjigeorgiou GM,Hattori N,Ioannidis JP,Boczarska-Jedynak M,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,Petrucci S,Puschmann A,Quattrone A,Sharma M,Silburn PA,Sohn YH,Stefanis L,Tadic V,Theuns J,Tomiyama H,Uitti RJ,Valente EM,Van Broeckhoven C,van de Loo S,Vassilatis DK,Vilariño-Güell C,White LR,Wirdefeldt K,Wszolek ZK,Wu RM,Hentati F,Farrer MJ,Ross OA,Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium

Abstract

Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.
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Large-scale replication and heterogeneity in Parkinson disease genetic loci.

Neurology 2012-08-14 79(7):659-67

Sharma M,Ioannidis JP,Aasly JO,Annesi G,Brice A,Van Broeckhoven C,Bertram L,Bozi M,Crosiers D,Clarke C,Facheris M,Farrer M,Garraux G,Gispert S,Auburger G,Vilariño-Güell C,Hadjigeorgiou GM,Hicks AA,Hattori N,Jeon B,Lesage S,Lill CM,Lin JJ,Lynch T,Lichtner P,Lang AE,Mok V,Jasinska-Myga B,Mellick GD,Morrison KE,Opala G,Pramstaller PP,Pichler I,Park SS,Quattrone A,Rogaeva E,Ross OA,Stefanis L,Stockton JD,Satake W,Silburn PA,Theuns J,Tan EK,Toda T,Tomiyama H,Uitti RJ,Wirdefeldt K,Wszolek Z,Xiromerisiou G,Yueh KC,Zhao Y,Gasser T,Maraganore D,Krüger R,GEO-PD Consortium

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.
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Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.

PLoS genetics 2012-07-22 8(3):e1002548

Lill CM,Roehr JT,McQueen MB,Kavvoura FK,Bagade S,Schjeide BM,Schjeide LM,Meissner E,Zauft U,Allen NC,Liu T,Schilling M,Anderson KJ,Beecham G,Berg D,Biernacka JM,Brice A,DeStefano AL,Do CB,Eriksson N,Factor SA,Farrer MJ,Foroud T,Gasser T,Hamza T,Hardy JA,Heutink P,Hill-Burns EM,Klein C,Latourelle JC,Maraganore DM,Martin ER,Martinez M,Myers RH,Nalls MA,Pankratz N,Payami H,Satake W,Scott WK,Sharma M,Singleton AB,Stefansson K,Toda T,Tung JY,Vance J,Wood NW,Zabetian CP,23andMe Genetic Epidemiology of Parkinson's Disease Consortium,International Parkinson's Disease Genomics Consortium,Parkinson's Disease GWAS Consortium,Wellcome Trust Case Control Consortium 2),Young P,Tanzi RE,Khoury MJ,Zipp F,Lehrach H,Ioannidis JP,Bertram L

Abstract

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P  =  1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
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Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.

Neurobiology of aging 2011-11-22 32(11):2108.e1-5

Sharma M,Maraganore DM,Ioannidis JP,Riess O,Aasly JO,Annesi G,Abahuni N,Bentivoglio AR,Brice A,Van Broeckhoven C,Chartier-Harlin MC,Destée A,Djarmati A,Elbaz A,Farrer M,Ferrarese C,Gibson JM,Gispert S,Hattori N,Jasinska-Myga B,Klein C,Lesage S,Lynch T,Lichtner P,Lambert JC,Lang AE,Mellick GD,De Nigris F,Opala G,Quattrone A,Riva C,Rogaeva E,Ross OA,Satake W,Silburn PA,Theuns J,Toda T,Tomiyama H,Uitti RJ,Wirdefeldt K,Wszolek Z,Gasser T,Krüger R,Genetic Epidemiology of Parkinson's Disease Consortium

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.
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Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

The Lancet. Neurology 2011-10-22 10(10):898-908

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,Theuns J,Tomiyama H,Uitti RJ,Valente EM,van de Loo S,Vassilatis DK,Vilariño-Güell C,White LR,Wirdefeldt K,Wszolek ZK,Wu RM,Farrer MJ,Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium

Abstract

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. 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. 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). 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. Michael J Fox Foundation and National Institutes of Health.
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Translation initiator EIF4G1 mutations in familial Parkinson disease.

American journal of human genetics 2011-09-09 89(3):398-406

Chartier-Harlin MC,Dachsel JC,Vilariño-Güell C,Lincoln SJ,Leprêtre F,Hulihan MM,Kachergus J,Milnerwood AJ,Tapia L,Song MS,Le Rhun E,Mutez E,Larvor L,Duflot A,Vanbesien-Mailliot C,Kreisler A,Ross OA,Nishioka K,Soto-Ortolaza AI,Cobb SA,Melrose HL,Behrouz B,Keeling BH,Bacon JA,Hentati E,Williams L,Yanagiya A,Sonenberg N,Lockhart PJ,Zubair AC,Uitti RJ,Aasly JO,Krygowska-Wajs A,Opala G,Wszolek ZK,Frigerio R,Maraganore DM,Gosal D,Lynch T,Hutchinson M,Bentivoglio AR,Valente EM,Nichols WC,Pankratz N,Foroud T,Gibson RA,Hentati F,Dickson DW,Destée A,Farrer MJ

Abstract

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.
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Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.

Annals of neurology 2011-05-22 69(5):778-92

Elbaz A,Ross OA,Ioannidis JP,Soto-Ortolaza AI,Moisan F,Aasly J,Annesi G,Bozi M,Brighina L,Chartier-Harlin MC,Destée A,Ferrarese C,Ferraris A,Gibson JM,Gispert S,Hadjigeorgiou GM,Jasinska-Myga B,Klein C,Krüger R,Lambert JC,Lohmann K,van de Loo S,Loriot MA,Lynch T,Mellick GD,Mutez E,Nilsson C,Opala G,Puschmann A,Quattrone A,Sharma M,Silburn PA,Stefanis L,Uitti RJ,Valente EM,Vilariño-Güell C,Wirdefeldt K,Wszolek ZK,Xiromerisiou G,Maraganore DM,Farrer MJ,Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium

Abstract

We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.
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A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.

Neurobiology of aging 2011-03-22 32(3):548.e9-18

Krüger R,Sharma M,Riess O,Gasser T,Van Broeckhoven C,Theuns J,Aasly J,Annesi G,Bentivoglio AR,Brice A,Djarmati A,Elbaz A,Farrer M,Ferrarese C,Gibson JM,Hadjigeorgiou GM,Hattori N,Ioannidis JP,Jasinska-Myga B,Klein C,Lambert JC,Lesage S,Lin JJ,Lynch T,Mellick GD,de Nigris F,Opala G,Prigione A,Quattrone A,Ross OA,Satake W,Silburn PA,Tan EK,Toda T,Tomiyama H,Wirdefeldt K,Wszolek Z,Xiromerisiou G,Maraganore DM,Genetic Epidemiology of Parkinson's disease consortium

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.
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Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson's disease: large-scale collaborative study.

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010-01-05 153B(1):220-8

Evangelou E,Maraganore DM,Annesi G,Brighina L,Brice A,Elbaz A,Ferrarese C,Hadjigeorgiou GM,Krueger R,Lambert JC,Lesage S,Markopoulou K,Mellick GD,Meeus B,Pedersen NL,Quattrone A,Van Broeckhoven C,Sharma M,Silburn PA,Tan EK,Wirdefeldt K,Ioannidis JP,Genetic Epidemiology of Parkinson's Disease (GEOPD) Consortium

Abstract

Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques.
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Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease.

PloS one 2007-02-07 2(2):e196

Evangelou E,Maraganore DM,Ioannidis JP

Abstract

Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1) enhancement of replication data and (2) enhancement of first-stage data, and then, we also considered (3) joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets) on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I(2) = 0, 0 and 15%, respectively). Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets). Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies.
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The emergence of networks in human genome epidemiology: challenges and opportunities.

Epidemiology (Cambridge, Mass.) 2007-01-22 18(1):1-8

Seminara D,Khoury MJ,O'Brien TR,Manolio T,Gwinn ML,Little J,Higgins JP,Bernstein JL,Boffetta P,Bondy M,Bray MS,Brenchley PE,Buffler PA,Casas JP,Chokkalingam AP,Danesh J,Davey Smith G,Dolan S,Duncan R,Gruis NA,Hashibe M,Hunter D,Jarvelin MR,Malmer B,Maraganore DM,Newton-Bishop JA,Riboli E,Salanti G,Taioli E,Timpson N,Uitterlinden AG,Vineis P,Wareham N,Winn DM,Zimmern R,Ioannidis JP,Human Genome Epidemiology Network,Network of Investigator Networks

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Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.

The Lancet. Neurology 2006-11-22 5(11):917-23

Elbaz A,Nelson LM,Payami H,Ioannidis JP,Fiske BK,Annesi G,Carmine Belin A,Factor SA,Ferrarese C,Hadjigeorgiou GM,Higgins DS,Kawakami H,Krüger R,Marder KS,Mayeux RP,Mellick GD,Nutt JG,Ritz B,Samii A,Tanner CM,Van Broeckhoven C,Van Den Eeden SK,Wirdefeldt K,Zabetian CP,Dehem M,Montimurro JS,Southwick A,Myers RM,Trikalinos TA

Abstract

A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.
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Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.

JAMA 2006-08-09 296(6):661-70

Maraganore DM,de Andrade M,Elbaz A,Farrer MJ,Ioannidis JP,Krüger R,Rocca WA,Schneider NK,Lesnick TG,Lincoln SJ,Hulihan MM,Aasly JO,Ashizawa T,Chartier-Harlin MC,Checkoway H,Ferrarese C,Hadjigeorgiou G,Hattori N,Kawakami H,Lambert JC,Lynch T,Mellick GD,Papapetropoulos S,Parsian A,Quattrone A,Riess O,Tan EK,Van Broeckhoven C,Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium

Abstract

Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.
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A road map for efficient and reliable human genome epidemiology.

Nature genetics 2006-01-22 38(1):3-5

Ioannidis JP,Gwinn M,Little J,Higgins JP,Bernstein JL,Boffetta P,Bondy M,Bray MS,Brenchley PE,Buffler PA,Casas JP,Chokkalingam A,Danesh J,Smith GD,Dolan S,Duncan R,Gruis NA,Hartge P,Hashibe M,Hunter DJ,Jarvelin MR,Malmer B,Maraganore DM,Newton-Bishop JA,O'Brien TR,Petersen G,Riboli E,Salanti G,Seminara D,Smeeth L,Taioli E,Timpson N,Uitterlinden AG,Vineis P,Wareham N,Winn DM,Zimmern R,Khoury MJ,Human Genome Epidemiology Network and the Network of Investigator Networks

Abstract

Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.
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A network of investigator networks in human genome epidemiology.

American journal of epidemiology 2005-08-15 162(4):302-4

Ioannidis JP,Bernstein J,Boffetta P,Danesh J,Dolan S,Hartge P,Hunter D,Inskip P,Jarvelin MR,Little J,Maraganore DM,Bishop JA,O'Brien TR,Petersen G,Riboli E,Seminara D,Taioli E,Uitterlinden AG,Vineis P,Winn DM,Salanti G,Higgins JP,Khoury MJ

Abstract

The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort.
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Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.

American journal of human genetics 2005-04-22 76(4):672-80

Kachergus J,Mata IF,Hulihan M,Taylor JP,Lincoln S,Aasly J,Gibson JM,Ross OA,Lynch T,Wiley J,Payami H,Nutt J,Maraganore DM,Czyzewski K,Styczynska M,Wszolek ZK,Farrer MJ,Toft M

Abstract

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.
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UCHL1 is a Parkinson's disease susceptibility gene.

Annals of neurology 2004-04-22 55(4):512-21

Maraganore DM,Lesnick TG,Elbaz A,Chartier-Harlin MC,Gasser T,Krüger R,Hattori N,Mellick GD,Quattrone A,Satoh J,Toda T,Wang J,Ioannidis JP,de Andrade M,Rocca WA,UCHL1 Global Genetics Consortium

Abstract

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.