title: Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.
abstract: BACKGROUND
  Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations.
  
  
  METHODS
  We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues.
  
  
  RESULTS
  In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology.
  
  
  CONCLUSIONS
  AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup; Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Bertelsen
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefánsson
authors.affiliation: Department of Human Genetics, University Medicine, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Riff Jensen
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup; Denmark.
authors.forename: Linea
authors.initials: L
authors.lastname: Melchior
authors.affiliation: Department of Pediatrics, Tourette Clinic, Herlev Hospital, Herlev.
authors.forename: Nanette
authors.initials: N
authors.lastname: Mol Debes
authors.affiliation: Department of Pediatrics, Tourette Clinic, Herlev Hospital, Herlev.
authors.forename: Camilla
authors.initials: C
authors.lastname: Groth
authors.affiliation: Department of Pediatrics, Tourette Clinic, Herlev Hospital, Herlev.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Skov
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre, Sct. Hans, Mental Health Services, Capital Region of Denmark, Hillerød; Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen; iPSYCH-The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Roskilde, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
authors.forename: Iordanis
authors.initials: I
authors.lastname: Karagiannidis
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup; Denmark.
authors.forename: Zsanett
authors.initials: Z
authors.lastname: Tarnok
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Barta
authors.affiliation: Vadaskert Child and Adolescent Psychiatry Clinic, Semmelweis University, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Vadaskert Child and Adolescent Psychiatry Clinic, Semmelweis University, Budapest, Hungary.
authors.forename: Luca
authors.initials: L
authors.lastname: Farkas
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup; Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Brøndum-Nielsen
authors.affiliation: Section of Child Neuropsychiatry, Department of Medical and Pediatric Sciences, Catania University, Catania, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Rizzo
authors.affiliation: Section of Child Neuropsychiatry, Department of Medical and Pediatric Sciences, Catania University, Catania, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Gulisano
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tosato
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Muhammad Sulaman
authors.initials: MS
authors.lastname: Nawaz
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Andres
authors.initials: A
authors.lastname: Ingason
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Unnsteinsdottir
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.affiliation: Department of Pediatrics, Landspitalinn University Hospital, Reykjavik, Iceland.
authors.forename: Pétur
authors.initials: P
authors.lastname: Ludvigsson
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Department of Human Genetics, University Medicine, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Andreas Walter
authors.initials: AW
authors.lastname: Kuss
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
authors.forename: Peristera
authors.initials: P
authors.lastname: Paschou
authors.affiliation: Department of Clinical and Health Psychology, Utrecht University & Altrecht Academic Anxiety Outpatient Clinics, Utrecht.
authors.forename: Danielle
authors.initials: D
authors.lastname: Cath
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
authors.affiliation: Clinic of Psychiatry, Social Psychiatry and Psychotherapy, and Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Müller-Vahl
authors.affiliation: Clinic of Psychiatry, Social Psychiatry and Psychotherapy, and Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Stuhrmann
authors.affiliation: Wilhelm Johansen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Asli
authors.initials: A
authors.lastname: Silahtaroglu
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Vadaskert Child and Adolescent Psychiatry Clinic, Semmelweis University, Budapest, Hungary. Electronic address: zeynep.tumer@regionh.dk.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
mesh_terms: D000328:Adult; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D015331:Cohort Studies; D015897:Comorbidity; D056915:DNA Copy Number Variations / Q000235:genetics*; D003718:Denmark; D005091:Exons; D005260:Female; D060005:Genotyping Techniques; D005858:Germany; D006801:Humans; D006814:Hungary; D007055:Iceland; D007558:Italy; D008297:Male; D051379:Mice; D009426:Netherlands; D017384:Sequence Deletion / Q000235:genetics*; D005879:Tourette Syndrome / Q000235:genetics*
keywords: AADAC; Association study; CNV; Copy number variation; Gilles de la Tourette syndrome; Neuropsychiatric disorder