Nicholas W Wood

Publications of Nicholas W Wood

• Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia.

  Authors: Georgios Koutsis, Sally Pemble, Mary G Sweeney, Reema Paudel, Nicholas W Wood, Marios Panas, Athina Kladi, Henry Houlden

  Journal of the neurological sciences. 04/2012;

  The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. NoThe relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified.

• Tau acts as an independent genetic risk factor in pathologically proven PD.

  Authors: Gavin Charlesworth, Sonia Gandhi, Jose M Bras, Roger A Barker, David J Burn, Patrick F Chinnery, Stephen M Gentleman, Rita Guerreiro, John Hardy, Janice L Holton, Andrew Lees, Karen Morrison, Una-Marie Sheerin, Nigel Williams, Huw Morris, Tamas Revesz, Nicholas W Wood

  Neurobiology of aging. 04/2012; 33(4):838.e7-838.e11.

  MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear.MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.

• Novel peripheral myelin protein 22 (PMP22) micromutations associated with variable phenotypes in Greek patients with Charcot-Marie-Tooth disease.

  Authors: Georgios Koutsis, Amelie Pandraud, James M Polke, Nicholas W Wood, Marios Panas, Georgia Karadima, Henry Houlden

  Brain : a journal of neurology. 03/2012;

• Hyposmia and cognitive impairment in Gaucher disease patients and carriers.

  Authors: Alisdair McNeill, Raquel Duran, Christos Proukakis, Jose Bras, Derralyn Hughes, Atuhl Mehta, John Hardy, Nicholas W Wood, Anthony H V Schapira

  Movement disorders : official journal of the Movement Disorder Society. 02/2012;

  The objective of this study was to assess a cohort of Gaucher disease patients and their heterozygous carrier relatives for potential clinical signs of early neurodegeneration. Gaucher diseaseThe objective of this study was to assess a cohort of Gaucher disease patients and their heterozygous carrier relatives for potential clinical signs of early neurodegeneration. Gaucher disease patients (n = 30), heterozygous glucocerebrosidase mutation carriers (n = 30), and mutation-negative controls matched by age, sex, and ethnicity (n = 30) were recruited. Assessment was done for olfactory function (University of Pennsylvania Smell Identification Test), cognitive function (Mini-Mental State Examination, Montreal Cognitive Assessment), rapid eye movement sleep disorder, autonomic symptoms, and parkinsonian motor signs (Unified Parkinson's Disease Rating Scale part III, Purdue pegboard). Olfactory function scores were significantly lower in Gaucher disease patients (P = .010) and heterozygous carriers (P < .001) than in controls. Cognitive assessment scores were significantly lower in Gaucher disease patients (P = .002) and carriers (P = .002) than in controls. Unified Parkinson's Disease Rating Scale motor subscale scores were significantly higher in Gaucher disease patients (P < .001) and heterozygotes (P = .0010) than in controls. There was no difference in scores for symptoms of rapid eye movement sleep disorder or autonomic dysfunction. Impairment of olfaction, cognition, and parkinsonian motor signs occurs more frequently in Gaucher disease patients and carriers than in controls, which may indicate the early stages of neurodegeneration. © 2012 Movement Disorder Society.

• Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

  Authors: Céline Bellenguez, Steve Bevan, Andreas Gschwendtner, Chris C A Spencer, Annette I Burgess, Matti Pirinen, Caroline A Jackson, Matthew Traylor, Amy Strange, Zhan Su [......] Agnieszka Slowik, Matthew Walters, Jonathan Rosand, Pankaj Sharma, Martin Farrall, Cathie L M Sudlow, Peter M Rothwell, Martin Dichgans, Peter Donnelly, Hugh S Markus

  Nature genetics. 01/2012; 44(3):328-333.

  Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes inGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

• Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease.

  Authors: Javier Simón-Sánchez, Laura L Kilarski, Michael A Nalls, Maria Martinez, Claudia Schulte, Peter Holmans, Thomas Gasser, John Hardy, Andrew B Singleton, Nicholas W Wood, Alexis Brice, Peter Heutink, Nigel Williams, Huw R Morris

  PloS one. 01/2012; 7(3):e28787.

  Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated withParkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity.We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort.There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis.

• Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease.

  Authors: Zhi Yao, Sonia Gandhi, Victoria S Burchell, Helene Plun-Favreau, Nicholas W Wood, Andrey Y Abramov

  Journal of cell science. 12/2011; 124(Pt 24):4194-202.

  Mitochondrial dysfunction plays a primary role in the pathogenesis of Parkinson's disease (PD), particularly in autosomal recessive forms of the disease caused by mutations encoding PINK1. AlthoughMitochondrial dysfunction plays a primary role in the pathogenesis of Parkinson's disease (PD), particularly in autosomal recessive forms of the disease caused by mutations encoding PINK1. Although mitochondrial pathology can be demonstrated in many cell types, it is neurons that bear the brunt of cell death in PD. We studied the mitochondrial physiology of neurons and muscle cells with loss of function of the nuclear encoded mitochondrial protein PINK1. PINK1 is widely expressed in many types of tissues, but deficiency selectively induces death in neurons. We report here that the same genetic defect results in opposing phenotypes in different cell types, depending on the metabolic properties of the cell. Thus, PINK1-deficient myocytes exhibit high basal mitochondrial membrane potential (Δψm), whereas PINK1-deficient neurons have been shown to exhibit a low Δψm. PINK1 deficiency induces impaired respiration in both cell types, with a concomitant increase in glycolytic activity. We demonstrate that the high glycolytic capacity in myocytes compared with neurons enables them to produce more ATP and, therefore, compensates for the metabolic defects induced by PINK1 deficiency. Furthermore, the high Δψm generated in PINK1 knockout (KO) muscle mitochondria enables them to buffer cytosolic Ca(2+) fluxes, rendering them resistant to Ca(2+) stress effectively. Conversely, PINK1 KO neurons were previously shown to develop mitochondrial Ca(2+) overload and Ca(2+)-induced mitochondrial depolarisation. Prevention of Ca(2+) dysregulation in myocytes might therefore account for the sparing of these cells in PD.

• Parkinson's disease and cancer: two wars, one front.

  Authors: Michael J Devine, Hélène Plun-Favreau, Nicholas W Wood

  Nature reviews. Cancer. 11/2011; 11(11):812-23.

  Parkinson's disease is caused by the premature death of neurons in the midbrain. By contrast, cancer spawns from cells that refuse to die. We would therefore expect their pathogenic mechanisms to beParkinson's disease is caused by the premature death of neurons in the midbrain. By contrast, cancer spawns from cells that refuse to die. We would therefore expect their pathogenic mechanisms to be very different. However, recent genetic studies and emerging functional work show that strikingly similar and overlapping pathways are involved in both diseases. We consider these areas of convergence and discuss how insights from one disease can inform us about, and possibly help us to treat, the other.

• Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

  Authors: Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C A Spencer, Nikolaos A Patsopoulos, Loukas Moutsianas, Alexander Dilthey, Zhan Su, Colin Freeman, Sarah E Hunt [......] Jan Hillert, Adrian J Ivinson, Philip L De Jager, Leena Peltonen, Graeme J Stewart, David A Hafler, Stephen L Hauser, Gil McVean, Peter Donnelly, Alastair Compston

  Nature. 08/2011; 476(7359):214-9.

  Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurologicalMultiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

  Download

• Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males.

  Authors: Christos Proukakis, David Moore, Robyn Labrum, Nicholas W Wood, Henry Houlden

  Journal of the neurological sciences. 07/2011; 306(1-2):62-5.

  Hereditary spastic paraplegia (HSP) is characterised in its pure form by slowly progressive spastic paraparesis. Around 40% of autosomal dominant (AD) cases are caused by mutations in SPAST, encodingHereditary spastic paraplegia (HSP) is characterised in its pure form by slowly progressive spastic paraparesis. Around 40% of autosomal dominant (AD) cases are caused by mutations in SPAST, encoding spastin. The clinical and investigation details of all patients with a SPAST mutation identified through our centre were reviewed. All published reports of SPAST mutations where the sex of patients was given were subsequently analysed in order to determine whether there is evidence of one sex being preferentially affected. In total 22 probable pathogenic changes were detected, including 11 novel ones. One patient carried two adjacent missense mutations. The pathogenicity of a further novel missense mutation is uncertain. Most patients had a pure phenotype, although mild peripheral neuropathy was sometimes present. The total number of patients with SPAST mutations was 27, as three of the previously known mutations were present in more than one person. The excess of males over females in our population (17:10) prompted us to review all published studies where the sex of the patients was given (n=31). A significant excess of males was identified (ratio 1.29, p=0.0007). Our results are consistent with data suggesting that SPAST mutations mostly cause a pure HSP phenotype. The excess of males in our sample and in published reports suggests that penetrance or severity may be sex-dependent, and merits further investigation as it may have important implications for counselling.

• Mitophagy and Parkinson's disease: the PINK1-parkin link.

  Authors: Emma Deas, Nicholas W Wood, Hélène Plun-Favreau

  Biochimica et biophysica acta. 04/2011; 1813(4):623-33.

  The study of rare, inherited mutations underlying familial forms of Parkinson's disease has provided insight into the molecular mechanisms of disease pathogenesis. Mutations in these genes have beenThe study of rare, inherited mutations underlying familial forms of Parkinson's disease has provided insight into the molecular mechanisms of disease pathogenesis. Mutations in these genes have been functionally linked to several key molecular pathways implicated in other neurodegenerative disorders, including mitochondrial dysfunction, protein accumulation and the autophagic-lysosomal pathway. In particular, the mitochondrial kinase PINK1 and the cytosolic E3 ubiquitin ligase parkin act in a common pathway to regulate mitochondrial function. In this review we discuss the recent evidence suggesting that the PINK1/parkin pathway also plays a critical role in the autophagic removal of damaged mitochondria-mitophagy. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.

• PINK1 cleavage at position A103 by the mitochondrial protease PARL.

  Authors: Emma Deas, Helene Plun-Favreau, Sonia Gandhi, Howard Desmond, Svend Kjaer, Samantha H Y Loh, Alan E M Renton, Robert J Harvey, Alexander J Whitworth, L Miguel Martins, Andrey Y Abramov, Nicholas W Wood

  Human molecular genetics. 03/2011; 20(5):867-79.

  Mutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known toMutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known to localize to mitochondria. Upon entry into the organelle, PINK1 is cleaved to produce a ∼53 kDa protein (ΔN-PINK1). In this paper, we show that PINK1 is cleaved between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1. We demonstrate that a reduced ability to cleave PINK1, and the consequent accumulation of full-length protein, results in mitochondrial abnormalities reminiscent of those observed in PINK1 knockout cells, including disruption of the mitochondrial network and a reduction in mitochondrial mass. Notably, we assessed three N-terminal PD-associated PINK1 mutations located close to the cleavage site and, while these do not prevent PINK1 cleavage, they alter the ratio of full-length to ΔN-PINK1 protein in cells, resulting in an altered mitochondrial phenotype. Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and that loss of PARL results in aberrant PINK1 cleavage in mammalian cells. These combined results suggest that PINK1 cleavage is important for basal mitochondrial health and that PARL cleaves PINK1 to produce the ΔN-PINK1 fragment.

• Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.

  Authors: Michael A Nalls, Vincent Plagnol, Dena G Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, J Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Kári Stefánsson, Maria Martinez, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B Singleton, Nicholas W Wood

  Lancet. 02/2011; 377(9766):641-9.

  Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. WeGenome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7-69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23-2·83) compared with 1·00 in the lowest quintile of disease risk. These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. Wellcome Trust, National Institute on Aging, and US Department of Defense.

• Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

  Authors: Kaixin Zhou, Celine Bellenguez, Chris C A Spencer, Amanda J Bennett, Ruth L Coleman, Roger Tavendale, Simon A Hawley, Louise A Donnelly, Chris Schofield, Christopher J Groves [......] Helen Colhoun, Andrew D Morris, Calum Sutherland, D Grahame Hardie, Leena Peltonen, Mark I McCarthy, Rury R Holman, Colin N A Palmer, Peter Donnelly, Ewan R Pearson

  Nature genetics. 02/2011; 43(2):117-20.

  Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

• An intragenic duplication in guanosine triphosphate cyclohydrolase-1 gene in a dopa-responsive dystonia family.

  Authors: Helen Ling, James M Polke, Mary G Sweeney, Andrea Haworth, Catherine A Sandford, Simon J R Heales, Nicholas W Wood, Mary B Davis, Andrew J Lees

  Movement disorders : official journal of the Movement Disorder Society. 02/2011; 26(5):905-9.

  Autosomal dominant dopa-responsive dystonia is commonly caused by mutations in the guanosine triphosphate cyclohydrolase-1 gene. We report a British family that has been followed for more than 20Autosomal dominant dopa-responsive dystonia is commonly caused by mutations in the guanosine triphosphate cyclohydrolase-1 gene. We report a British family that has been followed for more than 20 years in which no mutations were previously identified. Reanalysis of this pedigree detected a duplication of guanosine triphosphate cyclohydrolase-1 exon 2 in affected family members. mRNA analysis showed a mutant transcript with a tandem exon 2 duplication. Four family members developed dopa-responsive dystonia, with onset in their late teens, and subsequently developed restless leg syndrome and migraine. This is the first report of an intragenic guanosine triphosphate cyclohydrolase-1 duplication in a dopa-responsive dystonia family.

• Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21.

  Authors: Chris C A Spencer, Vincent Plagnol, Amy Strange, Michelle Gardner, Coro Paisan-Ruiz, Gavin Band, Roger A Barker, Celine Bellenguez, Kailash Bhatia, Hannah Blackburn [......] Simon Potter, Anna Rautanen, Stephen J Sawcer, Zhan Su, Richard C Trembath, Ananth C Viswanathan, Nigel W Williams, Huw R Morris, Peter Donnelly, Nicholas W Wood

  Human molecular genetics. 01/2011; 20(2):345-53.

  We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in anWe performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.

• Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.

  Authors: David M Evans, Chris C A Spencer, Jennifer J Pointon, Zhan Su, David Harvey, Grazyna Kochan, Udo Oppermann, Udo Opperman, Alexander Dilthey, Matti Pirinen [......] Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Nicholas W Wood, Gilean McVean, John D Reveille, B Paul Wordsworth, Matthew A Brown, Peter Donnelly

  Nature genetics. 01/2011; 43(8):761-7.

  Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we reportAnkylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

• Genetic variability at the PARK16 locus.

  Authors: Arianna Tucci, Mike A Nalls, Henry Houlden, Tamas Revesz, Andrew B Singleton, Nicholas W Wood, John Hardy, Coro Paisán-Ruiz

  European journal of human genetics : EJHG. 12/2010; 18(12):1356-9.

  Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra andParkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case-control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value=0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.

• Atypical parkinsonism with apraxia and supranuclear gaze abnormalities in type 1 Gaucher disease. Expanding the spectrum: case report and literature review.

  Authors: Araceli Alonso-Canovas, Petra Katschnig, Arianna Tucci, Miryam Carecchio, Nicholas W Wood, Mark Edwards, Juan Carlos Martínez Castrillo, Derek Burke, Simon Heales, Kailash P Bhatia

  Movement disorders : official journal of the Movement Disorder Society. 07/2010; 25(10):1506-9.

• Nonmotor symptoms in Parkin gene-related parkinsonism.

  Authors: Georg Kägi, Christine Klein, Nicholas W Wood, Susanne A Schneider, Peter P Pramstaller, Vera Tadic, Niall P Quinn, Bart P C van de Warrenburg, Kailash P Bhatia

  Movement disorders : official journal of the Movement Disorder Society. 07/2010; 25(9):1279-84.

  The aim of the study was to explore the prevalence and differences of nonmotor symptoms (NMSs) in patients with young-onset Parkinson's disease (YOPD) with and without mutations in the Parkin geneThe aim of the study was to explore the prevalence and differences of nonmotor symptoms (NMSs) in patients with young-onset Parkinson's disease (YOPD) with and without mutations in the Parkin gene and late-onset Parkinson's disease (LOPD). Twenty-seven patients with YOPD and 27 with LOPD, as well as 16 patients with homozygous or compound heterozygote Parkin mutations filled in the nonmotor symptoms questionnaire, a 30-item self-completed questionnaire that addresses various NMSs. Overall, NMSs were more prevalent in YOPD (12.07 +/- 3.9; P = 0.009) and LOPD (13.26 +/- 5.8; P = 0.001) compared with Parkin mutation carriers (7.38 +/- 4.2). Dribbling of saliva, vivid dreams, loss of smell, and urinary urgency were more prevalent in YOPD compared with Parkin mutation carriers. Only anxiety was more prevalent in the latter. Apart from anxiety, NMSs appear to be less prevalent in Parkin gene-related parkinsonism. Although these results need further study, the presented data might be helpful in the clinical recognition of specific phenotypes and genotypes in YOPD. The data are in keeping with a different pathological disease process in Parkin gene-related parkinsonism.