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. Author manuscript; available in PMC: 2018 Nov 13.
Published in final edited form as: Atten Defic Hyperact Disord. 2017 Feb 7;9(2):121–127. doi: 10.1007/s12402-017-0219-8

No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs

Julia M Geissler 1; International Parkinson Disease Genomics Consortium members, Marcel Romanos 1, Manfred Gerlach 1, Daniela Berg 2,3,4, Claudia Schulte 2,3
PMCID: PMC6233883  NIHMSID: NIHMS940138  PMID: 28176268

Abstract

Attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.

Keywords: ADHD, Parkinson’s disease, GWAS, SNPs, CDH13, Dopamine transporter

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a clinically heterogeneous neurodevelopmental syndrome with an onset in childhood, which persists at least partially into adulthood in up to 60% of patients (Gerlach and Romanos 2014). Patients with ADHD show characteristic symptoms of age-inappropriate inattention, impulsiveness and motor hyperactivity. Parkinson’s disease (PD) is a common and complex neurological disorder with age as a dominant risk factor. Prevalence and incidence increase nearly exponentially with age and peak after the age of 80 (Kalia and Lang 2015). PD has long been characterized by the classical motor symptoms such as bradykinesia, rigidity and/or resting tremor. However, PD is now recognized as a heterogeneous disease, with clinically significant non-motor features including olfactory dysfunction, cognitive impairment, psychiatric symptoms, sleep disorders and impulse control disorders (Kalia and Lang 2015).

There is increasing evidence from imaging studies that disturbances in cortico-basal ganglia-thalamo-cortical circuits may contribute to the development of motor, cognitive and impulsive symptoms seen in both ADHD and PD (Geng et al. 2006; Mehler-Wex et al. 2006: Gerlach and Romanos 2014; Volkmann et al. 2010). Cognitive and executive dysfunction is prevalent in both disorders (Craig et al. 2016; Goldman et al. 2015). Impulse control disorders including compulsive gambling, shopping, sexual behaviors and eating occur relatively frequently in PD (Ramirez-Zamora et al. 2016) and are often observed as an adverse reaction to PD treatment with dopaminergic drugs and deep brain stimulation of the subthalamic nucleus (for review, see Volkmann et al. 2010). Dopamine (DA) has long been known to be a crucial modulator of striatal processing of cortical and thalamic signals, mediated through glutamatergic synapses on the principal striatal neurons (medium spiny). Regulation of these neurons by DA is important for a wide array of psychomotor functions ascribed to the basal ganglia, including motor, cognitive and motivational functions. In PD, motor symptoms are largely the consequence of a progressive degeneration of cells in the pars compacta of the substantia nigra (SN), which constitute the nervous system’s most important DA suppliers (Gibb & Lees 1991). Abnormalities of the SN have also been demonstrated with transcranial sonography, with children with ADHD (Romanos et al. 2010) as well as PD patients (Berg et al. 2001) showing a hyperechogenic SN. Available symptomatic therapies for ADHD and PD both target the dopaminergic system (Gerlach and Romanos 2014; Walitza et al. 2014; Kalia and Lang 2015) by using drugs that enhance intracerebral DA concentrations and/or stimulate DA receptors.

The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions (Kalia and Lang 2015; Gerlach and Romanos 2014). Based on the common neurobiological pathways implicated in the development of motor, cognitive and impulsive symptoms seen in ADHD and PD, the aim of this study was to examine whether there is a genetic association between ADHD and PD. Interestingly, a recent study has shown that copy number variations at the PARK2 locus contribute to the genetic susceptibility to ADHD (Jarick et al. 2014). Mutations in the PARK2 gene have been reported to cause autosomal recessive juvenile PD (Crosiers et al. 2011). The PARK2 gene encodes parkin, which has been suggested to increase DA uptake by enhancing the ubiquitination and degradation of mis-folded DA transporter (Jiang et al. 2004).

Nine variants in seven genes were tested for association with PD based on an extensive literature review of genome-wide association studies (GWAS) and meta-analyses on ADHD involving single nucleotide polymorphisms (SNPs): four variants in the genes coding for synaptosomal-associated protein, 25kDa1 (SNAP25), the DA transporter (SLC6A3; DAT1), DA receptor D4 (DRD4) and serotonin receptor 1B (HTR1B) (Forero et al. 2009; Gizer et al. 2009), three SNPs in cadherin 13 (CDH13) (Lasky-Su et al. 2008; Lesch et al. 2008; Neale et al. 2010), and single SNPs located within the genes coding for tryptophan hydroxylase 2 (TPH2) and the noradrenaline transporter SLC6A2 (Park et al. 2013; Sengupta et al. 2012).

Materials and methods

We re-analyzed data from a recent meta-analysis of GWAS on PD (International Parkinson Disease Genomics Consortium 2011) specifically for association of risk variants in ADHD candidate genes with PD. The International Parkinson Disease Genomics Consortium (IPDGC) is an international collaboration of genome-wide association studies in PD. The total cohort comprised 5333 PD cases and 12,019 controls from European ancestry. This dataset included five GWA studies with patients and controls from the USA, the UK, France and Germany. All samples have been genotyped using Illumina platform and underwent extensive quality control criteria. Imputation has been performed using the Markov Chain-based haplotyper (version 1.0.16) yielding a total of 7,689,524 SNPs. GWAS have been undertaken using logistic regression models. Details on the cohort and analyses are published elsewhere (Spencer et al. 2011). Nine ADHD risk variants described above were tested for association with PD. Reported p values are not corrected for multiple testing.

Results

As listed in Table 1, the SNP rs1843809 in TPH2 was nominally associated with PD (uncorrected p = 0.037). Here, the more frequent T allele showed a protective effect, while the G allele was identified as risk variant. However, after using Bonferroni correction for multiple testing, the association became nonsignificant. None of the other analyzed variants showed a significant p value (Table 1). No substantial heterogeneity was detected in the analyzed cohort.

Table 1.

Results for attention-deficit/hyperactivity disorder candidate single nucleotide polymorphisms in Parkinson’s disease meta-analysis

Gene SNP Effect allele/other allele Allele frequency P value Effect Het p
CDH13 rs6565113 T/G 0.53 0.20  0.032 0.76
CDH13 rs11646411 C/G 0.88 0.92  0.004 0.73
CDH13 rs7187223 A/G 0.96 0.65 −0.028 0.58
DRD4 rs1800955 T/C 0.65 0.70 −0.0115 0.63
HTR1B rs6296 C/G 0.74 0.16  0.0405 0.45
SLC6A2 (NET1) rs3785143 T/C 0.091 0.958  0.0023 0.075
SLC6A3 (DAT1) rs27072 T/C 0.17 0.35 −0.031 0.33
SNAP25 rs3746544 T/G 0.65 0.97  9.00E-04 0.17
TPH2 rs1843809 T/G 0.85 0.037* −0.071 0.77
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*

Nominal significant; the shown p values are not corrected for multiple testing; Het p = heterogeneity p value; data derived from the PD meta-analysis (Nalls et al. 2011)

Discussion

Our hypothesis that risk variants in candidate genes for ADHD would also be significantly associated with PD could not be confirmed in this study.

ADHD is a developmental disorder with an onset in childhood, while PD is a degenerative disease associated with older age; ADHD and PD share abnormalities in cortico-basal ganglia-thalamo-cortical circuits, which contribute to motor, cognitive and impulsive symptoms in both disorders. The SNPs analyzed in our study were selected because they were located within genes coding for proteins that are involved in the regulation of dopaminergic, noradrenergic and serotonergic neurotransmission, which in turn is implicated in the development of motor, cognitive and impulsive symptoms seen in ADHD and PD. DAT1 is a presynaptically located protein that plays a key role in regulating the DA concentrations in the synaptic cleft by removing DA from the synaptic cleft and returning it to the presynaptic neurons (Giros et al. 1996). Reduced DAT1 density and reduced binding of the remaining DAT1 have been reported in the striatum of PD patients (Galvin 2006). In contrast, neuroimaging studies demonstrated an increased density of DAT1 in the striatum of ADHD patients (Fusar-Poli et al. 2012). SNAP25 constitutes part of the SNARE complex and is crucial for general neuro-transmitter release (for a review, see Rizo and Südhof 2002). A mutant mouse model of SNAP25 showed that the SNARE complex might be involved in the localization and accumulation of α-synuclein, a protein of unknown function that is located primarily in the presynaptic vesicles and modulates the DAT1 function (Sidhu et al. 2004). CDH13 propagates neuronal growth and brain plasticity. It is an interesting candidate for PD since it supports motility, growth and proliferation of neuronal cells (for a review, see Philippova et al. 2009) and is expressed in brain regions affected in PD (Takeuchi et al. 2000). Sequence variations in this gene may compromise the protein’s function as a negative regulator of axonal growth during development and its protective properties against oxidative stress (Philippova et al. 2009) and ultimately play a role in the progressive cell loss in PD.

It is conceivable that despite an underlying common genetic basis, the proposed genetic structure of most psychiatric disorders prevents the detection of contributing variants by means of GWAS. In psychiatric conditions, state-of-the-art genetic theories assume an interaction of a multitude of genes (both common and rare variants) with small effect. Precisely for this kind of genetic architecture, GWAS are ill-suited to detect the contributing variants. Hence, it is possible that genes showing up in GWAS on ADHD might be reflective of very specific forms of ADHD, where those variants are of high penetrance and immediate consequence and produce a distinct phenotype. The SNPs analyzed in our study were selected because they are situated within genes which code for products implicated in the etiopathogenesis of both disorders. Although no association survived correction for multiple testing, the putative roles of those genes for PD shall briefly be expanded upon. The negative finding regarding DAT1 is in line with a study on a Japanese sample, which could not confirm an association of the 3′ UTR VNTR polymorphism with PD, suggesting that the investigated polymorphism (Higuchi et al. 1995) is of limited importance for the etiopathogenesis of PD both in Asian and European populations. However, it has to be noted that there are some positive reports as well. Morino et al. (2000) found a nonfunctional base exchange in exon 9 (1215A/G) to be less common in PD, and there are reports of an association of other polymorphisms within this gene with the disorder (Juyal et al. 2006; Le Couteur et al. 1997).

However, putting our findings into perspective, there is doubt on common genetic bases in terms of variants with large effects for both PD and ADHD. Several independent lines of evidence support that conclusion. Firstly, a diagnosis of ADHD demands an early onset in childhood despite a high tendency to persist into adulthood, whereas PD patients typically experience the first symptoms late in life—the exception being rare recessive PD which typically has an early age of onset. It is conceivable that for ADHD—a disorder which emerges at a time where particularly the prefrontal cortex as the seat of cognitive control is still undergoing maturational processes (Shaw et al. 2006) and thus making it particularly vulnerable for disturbances—a different set of genes or genetic variants might be acting together to shape the developmental course of the brain. Furthermore, it is important to bear in mind that the two forms of PD have extremely different heritabilities, since most published GWAS on PD include only the sporadic and less strongly genetically triggered variant of the disorder, where a putative common genetic background is more complex. While familial PD shows relatively consistent associations with mutations in genes like SNCA encoding α-synuclein, PARK2, PINK1, PARK7 and LRRK2 (Lesage and Brice 2009), the predominant sporadic variant of the disorder seems more related to combinations of common variants within several genes. So it stands to reason that sporadic PD and the largely familial ADHD overall have divergent etiologies on a genetic level.

Conclusion

In a European sample, ADHD candidate SNPs within the genes coding for CDH13, DRD4, HTR1B, SLC6A2 (NET1), SLC6A3 (DAT1), SNAP25 and TPH2 were not associated with PD after correction for multiple testing. An overlap in the genetic architecture of both disorders cannot be ruled out, although traditional candidate genes in ADHD do not show a major effect in PD.

Acknowledgements

International Parkinson Disease Genomics Consortium members: Mike Nalls (Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA), Vincent Plagnol (UCL Genetics Institute, London, UK), Dena G Hernandez (Laboratory of Neurogenetics, National Institute on Aging; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK), Manu Sharma (Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany), Una-Marie Sheerin (Department of Molecular Neuroscience, UCL Institute of Neurology), Mohamad Saad (INSERM U563, CPTP, Toulouse, France; and Paul Sabatier University, Toulouse, France), Javier Simón-Sánchez (Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, Netherlands), Claudia Schulte (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Suzanne Lesage (INSERM, UMR_S975 [formerly UMR_S679], Paris, France; Université Pierre et Marie Curie-Paris, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Paris, France; and CNRS, Paris, France), Sigurlaug Sveinbjörnsdóttir (Department of Neurology, Landspítali University Hospital, Reykjavík, Iceland; Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, UK; and Queen Mary College, University of London, London, UK), Sampath Arepalli (Laboratory of Neurogenetics, National Institute on Aging), Roger Barker (Department of Neurology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK), Yoav Ben-Shlomo (School of Social and Community Medicine, University of Bristol), Henk W Berendse (Department of Neurology and Alzheimer Center, VU University Medical Center), Daniela Berg (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Kailash Bhatia (Department of Motor Neuroscience, UCL Institute of Neurology), Rob M A de Bie (Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands), Alessandro Biffi (Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA), Bas Bloem (Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands), Zoltan Bochdanovits (Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre), Michael Bonin (Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany), Jose M Bras (Department of Molecular Neuroscience, UCL Institute of Neurology), Kathrin Brockmann (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Janet Brooks (Laboratory of Neurogenetics, National Institute on Aging), David J Burn (Newcastle University Clinical Ageing Research Unit, Campus for Ageing and Vitality, Newcastle upon Tyne, UK), Gavin Charlesworth (Department of Molecular Neuroscience, UCL Institute of Neurology), Honglei Chen (Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA), Patrick F Chinnery (Neurology M4104, The Medical School, Framlington Place, Newcastle upon Tyne, UK), Sean Chong (Laboratory of Neurogenetics, National Institute on Aging), Carl E Clarke (School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK; and Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK), Mark R Cookson (Laboratory of Neurogenetics, National Institute on Aging), J Mark Cooper (Department of Clinical Neurosciences, UCL Institute of Neurology), Jean Christophe Corvol (INSERM, UMR_S975; Université Pierre et Marie Curie-Paris; CNRS; and INSERM CIC-9503, Hôpital Pitié-Salpêtrière, Paris, France), Carl Counsell (University of Aberdeen, Division of Applied Health Sciences, Population Health Section, Aberdeen, UK), Philippe Damier (CHU Nantes, CIC0004, Service de Neurologie, Nantes, France), Jean-François Dartigues (INSERM U897, Université Victor Segalen, Bordeaux, France), Panos Deloukas (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK), Günther Deuschl (Klinik für Neurologie, Universitätsklinikum SchleswigHolstein, Campus Kiel, Christian-Albrechts-Universität Kiel, Kiel, Germany), David T Dexter (Parkinson’s Disease Research Group, Faculty of Medicine, Imperial College London, London, UK), Karin D van Dijk (Department of Neurology and Alzheimer Center, VU University Medical Center), Allissa Dillman (Laboratory of Neurogenetics, National Institute on Aging), Frank Durif (Service de Neurologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France), Alexandra Dürr (INSERM, UMR_S975; Université Pierre et Marie Curie-Paris; CNRS; and AP-HP, Pitié-Salpêtrière Hospital), Sarah Edkins (Wellcome Trust Sanger Institute), Jonathan R Evans (Cambridge Centre for Brain Repair, Cambridge, UK), Thomas Foltynie (UCL Institute of Neurology), Jianjun Gao (Epidemiology Branch, National Institute of Environmental Health Sciences), Michelle Gardner (Department of Molecular Neuroscience, UCL Institute of Neurology), J Raphael Gibbs (Laboratory of Neurogenetics, National Institute on Aging; and Department of Molecular Neuroscience, UCL Institute of Neurology), Alison Goate (Department of Psychiatry, Department of Neurology, Washington University School of Medicine, MI, USA), Emma Gray (Wellcome Trust Sanger Institute), Rita Guerreiro (Department of Molecular Neuroscience, UCL Institute of Neurology), Omar Gustafsson (deCODE genetics and Department of Psychiatry, Oslo University Hospital, N-0407 Oslo, Norway), Clare Harris (University of Aberdeen), Jacobus J van Hilten (Department of Neurology, Leiden University Medical Center, Leiden, Netherlands), Albert Hofman (Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands), Albert Hollenbeck (AARP, Washington DC, USA), Janice Holton (Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology), Michele Hu (Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK), Xuemei Huang (Departments of Neurology, Radiology, Neurosurgery, Pharmacology, Kinesiology, and Bioengineering, Pennsylvania State University–Milton S Hershey Medical Center, Hershey, PA, USA), Heiko Huber (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Gavin Hudson (Neurology M4104, The Medical School, Newcastle upon Tyne, UK), Sarah E Hunt (Wellcome Trust Sanger Institute), Johanna Huttenlocher (deCODE genetics), Thomas Illig (Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany), Pálmi V Jónsson (Department of Geriatrics, Landspítali University Hospital, Reykjavík, Iceland), Jean-Charles Lambert (INSERM U744, Lille, France; and Institut Pasteur de Lille, Université de Lille Nord, Lille, France), Cordelia Langford (Cambridge Centre for Brain Repair), Andrew Lees (Queen Square Brain Bank for Neurological Disorders), Peter Lichtner (Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany), Patricia Limousin (Institute of Neurology, Sobell Department, Unit of Functional Neurosurgery, London, UK), Grisel Lopez (Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health), Delia Lorenz (Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein), Alisdair McNeill (Department of Clinical Neurosciences, UCL Institute of Neurology), Catriona Moorby (School of Clinical and Experimental Medicine, University of Birmingham), Matthew Moore (Laboratory of Neurogenetics, National Institute on Aging), Huw R Morris (MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK), Karen E Morrison (School of Clinical and Experimental Medicine, University of Birmingham; and Neurosciences Department, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK), Ese Mudanohwo (Neurogenetics Unit, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery), Sean S O’Sullivan (Queen Square Brain Bank for Neurological Disorders), Justin Pearson (MRC Centre for Neuropsychiatric Genetics and Genomics), Joel S Perlmutter (Department of Neurology, Radiology, and Neurobiology at Washington University, St Louis), Hjörvar Pétursson (deCODE genetics; and Department of Medical Genetics, Institute of Human Genetics, University of Tübingen), Pierre Pollak (Service de Neurologie, CHU de Grenoble, Grenoble, France), Bart Post (Department of Neurology, Radboud University Nijmegen Medical Centre), Simon Potter (Wellcome Trust Sanger Institute), Bernard Ravina (Translational Neurology, Biogen Idec, MA, USA), Tamas Revesz (Queen Square Brain Bank for Neurological Disorders), Olaf Riess (Department of Medical Genetics, Institute of Human Genetics, University of Tübingen), Fernando Rivadeneira (Departments of Epidemiology and Internal Medicine, Erasmus University Medical Center), Patrizia Rizzu (Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre), Mina Ryten (Department of Molecular Neuroscience, UCL Institute of Neurology), Stephen Sawcer (University of Cambridge, Department of Clinical Neurosciences, Addenbrooke’s hospital, Cambridge, UK), Anthony Schapira (Department of Clinical Neurosciences, UCL Institute of Neurology), Hans Scheffer (Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands), Karen Shaw (Queen Square Brain Bank for Neurological Disorders), Ira Shoulson (Department of Neurology, University of Rochester, Rochester, NY, USA), Ellen Sidransky (Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI), Colin Smith (Department of Pathology, University of Edinburgh, Edinburgh, UK), Chris C A Spencer (Wellcome Trust Centre for Human Genetics, Oxford, UK), Hreinn Stefánsson (deCODE genetics), Stacy Steinberg (deCODE genetics), Joanna D Stockton (School of Clinical and Experimental Medicine), Amy Strange (Wellcome Trust Centre for Human Genetics), Kevin Talbot (University of Oxford, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK), Carlie M Tanner (Clinical Research Department, The Parkinson’s Institute and Clinical Center, Sunnyvale, CA, USA), Avazeh Tashakkori-Ghanbaria (Wellcome Trust Sanger Institute), François Tison (Service de Neurologie, Hôpital Haut-Lévêque, Pessac, France), Daniah Trabzuni (Department of Molecular Neuroscience, UCL Institute of Neurology), Bryan J Traynor (Laboratory of Neurogenetics, National Institute on Aging), André G Uitterlinden (Departments of Epidemiology and Internal Medicine, Erasmus University Medical Center), Daan Velseboer (Department of Neurology, Academic Medical Center), Marie Vidailhet (INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225), Robert Walker (Department of Pathology, University of Edinburgh), Bart van de Warrenburg (Department of Neurology, Radboud University Nijmegen Medical Centre), Mirdhu Wickremaratchi (Department of Neurology, Cardiff University, Cardiff, UK), Nigel Williams (MRC Centre for Neuropsychiatric Genetics and Genomics), Caroline H Williams-Gray (Department of Neurology, Addenbrooke’s Hospital), Sophie Winder-Rhodes (Department of Psychiatry and Medical Research Council and Wellcome Trust Behavioural and Clinical Neurosciences Institute, University of Cambridge), Kári Stefánsson (deCODE genetics), Maria Martinez (INSERM U563; and Paul Sabatier University), John Hardy (Department of Molecular Neuroscience, UCL Institute of Neurology), Peter Heutink (Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre), Alexis Brice (INSERM, UMR_S975, Université Pierre et Marie Curie-Paris, CNRS, UMR 7225, AP-HP, Pitié-Salpêtrière Hospital). Wellcome Trust Case-Control Consortium 2 (webappendix p 13): Thomas Gasser (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, and DZNE, German Center for Neurodegenerative Diseases), Andrew B Singleton (Laboratory of Neurogenetics, National Institute on Aging), Nicholas W Wood (UCL Genetics Institute; and Department of Molecular Neuroscience, UCL Institute of Neurology).

Footnotes

Compliance with ethical standards

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards All studies contributing data for this publication have been approved by the local ethics committees and were performed in accordance with the 1964 Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from all participants prior to their inclusion in the study.

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