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1.  Large-scale replication and heterogeneity in Parkinson disease genetic loci 
Sharma, Manu | Ioannidis, John P.A. | Aasly, Jan O. | Annesi, Grazia | Brice, Alexis | Van Broeckhoven, Christine | Bertram, Lars | Bozi, Maria | Crosiers, David | Clarke, Carl | Facheris, Maurizio | Farrer, Matthew | Garraux, Gaetan | Gispert, Suzana | Auburger, Georg | Vilariño-Güell, Carles | Hadjigeorgiou, Georgios M. | Hicks, Andrew A. | Hattori, Nobutaka | Jeon, Beom | Lesage, Suzanne | Lill, Christina M. | Lin, Juei-Jueng | Lynch, Timothy | Lichtner, Peter | Lang, Anthony E. | Mok, Vincent | Jasinska-Myga, Barbara | Mellick, George D. | Morrison, Karen E. | Opala, Grzegorz | Pramstaller, Peter P. | Pichler, Irene | Park, Sung Sup | Quattrone, Aldo | Rogaeva, Ekaterina | Ross, Owen A. | Stefanis, Leonidas | Stockton, Joanne D. | Satake, Wataru | Silburn, Peter A. | Theuns, Jessie | Tan, Eng-King | Toda, Tatsushi | Tomiyama, Hiroyuki | Uitti, Ryan J. | Wirdefeldt, Karin | Wszolek, Zbigniew | Xiromerisiou, Georgia | Yueh, Kuo-Chu | Zhao, Yi | Gasser, Thomas | Maraganore, Demetrius | Krüger, Rejko | Boyle, R.S | Sellbach, A | O'Sullivan, J.D. | Sutherland, G.T. | Siebert, G.A | Dissanayaka, N.N.W | Van Broeckhoven, Christine | Theuns, Jessie | Crosiers, David | Pickut, Barbara | Engelborghs, Sebastiaan | Meeus, Bram | De Deyn, Peter P. | Cras, Patrick | Rogaeva, Ekaterina | Lang, Anthony E | Agid, Y | Anheim, M | Bonnet, A-M | Borg, M | Brice, A | Broussolle, E | Corvol, JC | Damier, P | Destée, A | Dürr, A | Durif, F | Lesage, S | Lohmann, E | Pollak, P | Rascol, O | Tison, F | Tranchant, C | Viallet, F | Vidailhet, M | Tzourio, Christophe | Amouyel, Philippe | Loriot, Marie-Anne | Mutez, Eugénie | Duflot, Aurélie | Legendre, Jean-Philippe | Waucquier, Nawal | Gasser, Thomas | Riess, Olaf | Berg, Daniela | Schulte, Claudia | Klein, Christine | Djarmati, Ana | Hagenah, Johann | Lohmann, Katja | Auburger, Georg | Hilker, Rüdiger | van de Loo, Simone | Dardiotis, Efthimios | Tsimourtou, Vaia | Ralli, Styliani | Kountra, Persa | Patramani, Gianna | Vogiatzi, Cristina | Hattori, Nobutaka | Tomiyama, Hiroyuki | Funayama, Manabu | Yoshino, Hiroyo | Li, Yuanzhe | Imamichi, Yoko | Toda, Tatsushi | Satake, Wataru | Lynch, Tim | Gibson, J. Mark | Valente, Enza Maria | Ferraris, Alessandro | Dallapiccola, Bruno | Ialongo, Tamara | Brighina, Laura | Corradi, Barbara | Piolti, Roberto | Tarantino, Patrizia | Annesi, Ferdinanda | Jeon, Beom S. | Park, Sung-Sup | Aasly, J | Opala, Grzegorz | Jasinska-Myga, Barbara | Klodowska-Duda, Gabriela | Boczarska-Jedynak, Magdalena | Tan, Eng King | Belin, Andrea Carmine | Olson, Lars | Galter, Dagmar | Westerlund, Marie | Sydow, Olof | Nilsson, Christer | Puschmann, Andreas | Lin, JJ | Maraganore, Demetrius M. | Ahlskog, J, Eric | de Andrade, Mariza | Lesnick, Timothy G. | Rocca, Walter A. | Checkoway, Harvey | Ross, Owen A | Wszolek, Zbigniew K. | Uitti, Ryan J.
Neurology  2012;79(7):659-667.
Objective:
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.
Methods:
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.
Results:
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 (I2 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.
Conclusion:
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® 2012;79:659–667
doi:10.1212/WNL.0b013e318264e353
PMCID: PMC3414661  PMID: 22786590
2.  Genetics of Vascular Dementia 
Minerva psichiatrica  2010;51(1):9-25.
Genetic studies are transforming the way we diagnose, evaluate and treat patients. The era of genome-wide association studies promised to discover common risk variants in heterogeneous disorders where previous small-scale association studies had on the whole failed. However, as we enter the post-association era a degree of disappoint is felt regarding the lack of risk factors with large effect for a number of disorders including vascular disease. Vascular disorders are sporadic by nature, though a familial component has been observed. This review will focus on vascular dementia, the genetic risk factors for vascular disorders and highlight how new technologies may overcome the limitations of genome-wide association and nominate those genes that influence disease risk.
PMCID: PMC4332411
3.  The protective effect of LRRK2 p.R1398H on risk of Parkinson’s disease is independent of MAPT and SNCA variants 
Neurobiology of aging  2013;35(1):10.1016/j.neurobiolaging.2013.07.013.
The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-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 four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) 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 PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
doi:10.1016/j.neurobiolaging.2013.07.013
PMCID: PMC3829604  PMID: 23962496
Parkinson disease; LRRK2; SNCA; MAPT; interaction; genetics
4.  Update on novel familial forms of Parkinson’s disease and multiple system atrophy 
Parkinsonism & related disorders  2014;20(0 1):S29-S34.
Parkinson’s disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.
doi:10.1016/S1353-8020(13)70010-5
PMCID: PMC4215194  PMID: 24262183
SNCA; VPS35; PD; MSA; Genetics; Familial
5.  Patient-Control Association Study of the LRRK2 Gene in South African Parkinson’s Disease Patients 
doi:10.1002/mds.25637
PMCID: PMC3859714  PMID: 24014121
Parkinson’s disease; LRRK2 gene; case-control association studies; South African population
6.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human molecular genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
doi:10.1093/hmg/ddu334
PMCID: PMC4222357  PMID: 24973356
7.  Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease 
Neurology  2014;83(21):1906-1913.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0000000000001012
PMCID: PMC4248456  PMID: 25326098
8.  Analysis of Nuclear Export Sequence Regions of FUS-Related RNA-Binding Proteins in Essential Tremor 
PLoS ONE  2014;9(11):e111989.
Background and Objective
Genes encoding RNA-binding proteins, including FUS and TDP43, play a central role in different neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Recently, a mutation located in the nuclear export signal (NES) of the FUS gene has been reported to cause an autosomal dominant form of familial Essential tremor.
Material and Methods
We sequenced the exons coding the NES domains of five RNA-binding proteins (TARDBP, hnRNPA2B1, hnRNPA1, TAF15 and EWSR1) that have been previously implicated in neurodegeneration in a series of 257 essential tremor (ET) cases and 376 healthy controls. We genotyped 404 additional ET subjects and 510 healthy controls to assess the frequency of the EWSR1 p.R471C substitution.
Results
We identified a rare EWSR1 p.R471C substitution, which is highly conserved, in a single subject with familial ET. The pathogenicity of this substitution remains equivocal, as DNA samples from relatives were not available and the genotyping of 404 additional ET subjects did not reveal any further carriers. No other variants were observed with significant allele frequency differences compared to controls in the NES coding regions.
Conclusions
The present study demonstrates that the NES domains of RNA-binding proteins are highly conserved. The role of the EWSR1 p.R471C substitution needs to be further evaluated in future studies.
doi:10.1371/journal.pone.0111989
PMCID: PMC4222957  PMID: 25375143
9.  Analysis of COQ2 gene in multiple system atrophy 
Background
Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.
Results
We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.
Conclusions
The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-44) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-44
PMCID: PMC4233093  PMID: 25373618
COQ2; Multiple system atrophy; Genetics; CoQ10 deficiency
10.  Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease 
Parkinsonism & related disorders  2013;19(11):1057-1060.
Objective
Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin.
Methods
Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function.
Results
We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants.
Conclusions
Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.
doi:10.1016/j.parkreldis.2013.07.011
PMCID: PMC4055791  PMID: 23916651
α-synuclein; SNCA gene; Parkinson's disease; Genetic etiology; Missense mutations
11.  Alpha-synuclein and tau: teammates in neurodegeneration? 
The accumulation of α-synuclein aggregates is the hallmark of Parkinson’s disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, α-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and α-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.
doi:10.1186/1750-1326-9-43
PMCID: PMC4230508  PMID: 25352339
Tau; MAPT; Synuclein; SNCA; Oligomers; Tangles; Synucleinopathy; Tauopathy; Parkinson’s disease; Alzheimer’s disease
12.  Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations 
Parkinsonism & related disorders  2013;19(10):869-877.
Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies including leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.
We studied neuropathologically verified HDLS patients with CSF1R mutations to assess Parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with Parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11).
We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of Parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.
doi:10.1016/j.parkreldis.2013.05.013
PMCID: PMC3977389  PMID: 23787135
HDLS; CSF1R mutation; Parkinsonism; Autosomal dominant; White matter disorders
13.  Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology Of Parkinson’s Disease (GEO-PD) consortium 
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 susceptibility to disease displays many features that reflect the nature of complex late-onset sporadic disorders, such as 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) reported in the original publication. Simple population allele frequencies can not only provide an insight into the clinical relevance of specific variants but also help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles incorporating both risk and protective factors will determine future diagnostic and treatment strategies.
doi:10.1002/mds.25600
PMCID: PMC4108155  PMID: 23913756
Parkinson disease; LRRK2; genetics; association study
14.  Investigating the role of FUS exonic variants in Essential Tremor 
Parkinsonism & related disorders  2013;19(8):755-757.
Essential Tremor is the most common form of movement disorder. Aggregation in families suggests a strong genetic component to disease. Linkage and association studies have identified several risk loci but the specific causal variants are still unknown. A recent study using whole exome sequencing identified a rare nonsense variant in the FUS gene (p.Q290X) that segregated with Essential Tremor in a large French Canadian family. In addition, two other rare FUS variants were identified (p.R216C and p.P431L) in Essential Tremor patients however co-segregation analysis with disease was not possible. In the present study, we sequenced all 15 exons of FUS in 152 familial probands with Essential Tremor and genotyped three reported FUS variants in 112 sporadic Essential Tremor patients and 716 control subjects recruited at Mayo Clinic Florida. Only known synonymous SNPs unlikely to be pathogenic were detected in our sequencing and not any of the recently identified mutations or novel ones. We conclude that the FUS mutations associated with risk of Essential Tremor are probably a rare occurrence.
doi:10.1016/j.parkreldis.2013.03.005
PMCID: PMC3691340  PMID: 23601511
Essential tremor; Fused in Sarcoma; Parkinson disease; genetic
15.  Association Studies of Sporadic Parkinson’s Disease in the Genomic Era 
Current Genomics  2014;15(1):2-10.
Parkinson’s disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson’s disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson’s disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.
doi:10.2174/1389202914666131210212745
PMCID: PMC3958956  PMID: 24653658
Sporadic Parkinson’s disease; Genetics; Genome-wide association studies.
16.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human Molecular Genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
doi:10.1093/hmg/ddu334
PMCID: PMC4222357  PMID: 24973356
17.  Similarities between familial and sporadic autopsy-proven progressive supranuclear palsy 
Neurology  2013;80(22):2076-2078.
Progressive supranuclear palsy (PSP) is a relatively common neurodegenerative tauopathy clinically characterized by parkinsonism, axial rigidity, and supranuclear gaze palsy. Pathologic findings of PSP are neuronal loss, gliosis, and neurofibrillary tangles in basal ganglia, diencephalon, and brainstem; there is increasing recognition of clinicopathologic variants of PSP.1
doi:10.1212/WNL.0b013e318294b2eb
PMCID: PMC3716405  PMID: 23635960
18.  Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age 
Deelen, Joris | Beekman, Marian | Uh, Hae-Won | Broer, Linda | Ayers, Kristin L. | Tan, Qihua | Kamatani, Yoichiro | Bennet, Anna M. | Tamm, Riin | Trompet, Stella | Guðbjartsson, Daníel F. | Flachsbart, Friederike | Rose, Giuseppina | Viktorin, Alexander | Fischer, Krista | Nygaard, Marianne | Cordell, Heather J. | Crocco, Paolina | van den Akker, Erik B. | Böhringer, Stefan | Helmer, Quinta | Nelson, Christopher P. | Saunders, Gary I. | Alver, Maris | Andersen-Ranberg, Karen | Breen, Marie E. | van der Breggen, Ruud | Caliebe, Amke | Capri, Miriam | Cevenini, Elisa | Collerton, Joanna C. | Dato, Serena | Davies, Karen | Ford, Ian | Gampe, Jutta | Garagnani, Paolo | de Geus, Eco J.C. | Harrow, Jennifer | van Heemst, Diana | Heijmans, Bastiaan T. | Heinsen, Femke-Anouska | Hottenga, Jouke-Jan | Hofman, Albert | Jeune, Bernard | Jonsson, Palmi V. | Lathrop, Mark | Lechner, Doris | Martin-Ruiz, Carmen | Mcnerlan, Susan E. | Mihailov, Evelin | Montesanto, Alberto | Mooijaart, Simon P. | Murphy, Anne | Nohr, Ellen A. | Paternoster, Lavinia | Postmus, Iris | Rivadeneira, Fernando | Ross, Owen A. | Salvioli, Stefano | Sattar, Naveed | Schreiber, Stefan | Stefánsson, Hreinn | Stott, David J. | Tiemeier, Henning | Uitterlinden, André G. | Westendorp, Rudi G.J. | Willemsen, Gonneke | Samani, Nilesh J. | Galan, Pilar | Sørensen, Thorkild I.A. | Boomsma, Dorret I. | Jukema, J. Wouter | Rea, Irene Maeve | Passarino, Giuseppe | de Craen, Anton J.M. | Christensen, Kaare | Nebel, Almut | Stefánsson, Kári | Metspalu, Andres | Magnusson, Patrik | Blanché, Hélène | Christiansen, Lene | Kirkwood, Thomas B.L. | van Duijn, Cornelia M. | Franceschi, Claudio | Houwing-Duistermaat, Jeanine J. | Slagboom, P. Eline
Human Molecular Genetics  2014;23(16):4420-4432.
The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
doi:10.1093/hmg/ddu139
PMCID: PMC4103672  PMID: 24688116
19.  Frequency of APOE, MTHFR and ACE polymorphisms in the Zambian population 
BMC Research Notes  2014;7:194.
Background
Polymorphisms within the apolipoprotein-E (APOE), Methylenetetrahydrofolate reductase (MTHFR) and Angiotensin I-converting enzyme (ACE) genes has been associated with cardiovascular and cerebrovascular disorders, Alzheimer’s disease and other complex diseases in various populations. The aim of the study was to analyze the allelic and genotypic frequencies of APOE, MTHFR C677T and ACE I/D gene polymorphisms in the Zambian population.
Results
The allele frequencies of APOE polymorphism in the Zambian populations were 13.8%, 59.5% and 26.7% for the ε2, ε3 and ε4 alleles respectively. MTHFR C677T and ACE I/D allele frequencies were 8.6% and 13.8% for the T and D minor alleles respectively. The ε2ε2 genotype and TT genotype were absent in the Zambian population. The genetic distances between Zambian and other African and non-African major populations revealed an independent variability of these polymorphisms.
Conclusion
We found that the APOE ε3 allele and the I allele of the ACE were significantly high in our study population while there were low frequencies observed for the MTHFR 677 T and ACE D alleles. Our analysis of the APOE, MTHFR and ACE polymorphisms may provide valuable insight into the understanding of the disease risk in the Zambian population.
doi:10.1186/1756-0500-7-194
PMCID: PMC4230427  PMID: 24679048
Sub-Saharan Africa; Zambia; Frequency; APOE; MTHFR; ACE polymorphisms
20.  ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease 
Recent genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these “actionable” variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D’ = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5×10−05; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D’ = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
doi:10.1186/1750-1326-9-11
PMCID: PMC3995879  PMID: 24607147
21.  Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia 
Acta neuropathologica  2012;125(3):425-438.
We recently reported a missense mutation and four variants in eukaryotic translation initiation factor 4-gamma (EIF4G1) associated with parkinsonism, dementia or both. In those with a positive family history, the mode of inheritance was autosomal dominant. Detailed neuropathologic descriptions of individuals with EIF4G1 genetic variants have not been reported. Herein, we report neuropathologic findings of three individuals from two American families with EIF4G1 variants. The patients had initial clinical presentations of dementia or parkinsonism and all had dementia at the time of autopsy. One family carried an EIF4G1 double variant, c.2056G>T (p.G686C) and c.3589C>T (p.R1197W), and one family carried variant c.1505C>T (p.A502V). All three patients also carried at least one ε4 allele of apolipoprotein E. One individual presented with cognitive impairment without significant parkinsonism; one presented with memory problems followed by bradykinesia; and the third presented with cardinal signs of Parkinson’s disease, followed more than a year later by cognitive dysfunction. Pathological examination showed diffuse cortical Lewy bodies and Lewy neurites in all patients. A small subset of Lewy bodies and Lewy neurites were immunopositive for eIF4G1. All patients had moderate to frequent non-neuritic, cortical amyloid plaques, mostly medial temporal neurofibrillary pathology (Braak neurofibrillary tangle stages of II to IV), and minimal or no TDP-43 pathology. The results suggest that in some patients variants in EIF4G1 can be associated with pathology that has a high likelihood of association with clinical features of dementia with Lewy bodies.
doi:10.1007/s00401-012-1059-4
PMCID: PMC3580022  PMID: 23124435
APOE; dementia with Lewy bodies; diffuse Lewy body disease; EIF4G1; parkinsonism; α-synuclein; tau
22.  Common Variants within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage 
Background and Purpose
Prior studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH).
Methods
This association study employed a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis (GSEA) was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing GSEA were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts.
Results
IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio (OR)=1.17, p=0.008) and Complex I (OR=1.06, p=0.050). Among IS subtypes, small vessel (SV) stroke showed association with OXPHOS (OR=1.16, p=0.007), Complex I (OR=1.13, p=0.027) and Complex IV (OR 1.14, p=0.018). To further explore this SV association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and Complex IV (OR=1.08, p=0.008).
Conclusions
This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for SV stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences.
doi:10.1161/STROKEAHA.112.672089
PMCID: PMC3582722  PMID: 23362085
OXPHOS; mitochondria; stroke; genes
23.  TARDBP mutations in Parkinson’s disease 
Parkinsonism & related disorders  2012;19(3):312-315.
Mutations of the TARDBP gene encoding TDP-43 protein have been shown to cause amyotrophic lateral sclerosis and have been reported to present with clinical heterogeneity including parkinsonism. In addition, TDP-43 pathology has been observed across a spectrum of neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Herein we report the presence of a TDP-43 mutation in a patient with a clinical diagnosis of Parkinson’s disease. The TDP-43 p.N267S substitution has been previously implicated in both amyotrophic lateral sclerosis and behavioral variant frontotemporal dementia. Our findings widen the phenotypic presentation for the TDP-43 p.N267S substitution and support a possible role for rare TDP-43 mutations presenting with Parkinson’s disease.
doi:10.1016/j.parkreldis.2012.11.003
PMCID: PMC3582838  PMID: 23231971
TDP-43; amyotrophic lateral sclerosis; Parkinson’s disease
24.  A prognostic view on the application of individualized genomics in Parkinson’s disease 
Parkinson’s disease is a common age-related progressive neurodegenerative disorder. Over the last 15 years advances have been made in our understanding of the etiology of the disease, with the greatest insights perhaps coming from genetic studies. The identification of a number of genes that harbor pathogenic mutations causing Parkinson’s disease have on the whole driven the development of disease model systems and nominated a number of therapeutic targets. As we move towards an era of personalized medicine, genetic determinants will become even more crucial for accurate diagnosis, and assessing prognosis and outcomes. The individual genomic profile and risk assessments will in the long-term determine clinical trial participation, treatment plans and therapeutic dosing. Herein we discuss the status of genetics in Parkinson’s disease and how these factors may affect the patient care in the future.
doi:10.1007/s40142-012-0003-1
PMCID: PMC3596092  PMID: 23504498
Parkinson’s disease; genetics; diagnosis; individualized medicine; genomics
25.  LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease 
Neurogenetics  2010;11(4):401-408.
Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n=95; PD, n=96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n=1,247; PD, n=633) and controls (n=642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR)=0.63; P=0.026) and PD (OR=0.54; P=0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P<0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P<0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.
doi:10.1007/s10048-010-0241-x
PMCID: PMC3930084  PMID: 20369371
Essential tremor; Parkinson disease; LINGO1; LINGO2; Genetic association

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