Birgitte Bertelsen1, Hreinn Stefánsson2, Lars Riff Jensen3, Linea Melchior1, Nanette Mol Debes4, Camilla Groth4, Liselotte Skov4, Thomas Werge5, Iordanis Karagiannidis6, Zsanett Tarnok1, Csaba Barta7, Peter Nagy8, Luca Farkas8, Karen Brøndum-Nielsen1, Renata Rizzo9, Mariangela Gulisano9, Dan Rujescu10, Lambertus A Kiemeney11, Sarah Tosato12, Muhammad Sulaman Nawaz2, Andres Ingason2, Unnur Unnsteinsdottir2, Stacy Steinberg2, Pétur Ludvigsson13, Kari Stefansson2, Andreas Walter Kuss3, Peristera Paschou6, Danielle Cath14, Pieter J Hoekstra15, Kirsten Müller-Vahl16, Manfred Stuhrmann16, Asli Silahtaroglu17, Rolph Pfundt18, Zeynep Tümer19. 1. Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup; Denmark. 2. deCODE Genetics, Reykjavik, Iceland. 3. Department of Human Genetics, University Medicine, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany. 4. Department of Pediatrics, Tourette Clinic, Herlev Hospital, Herlev. 5. 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. 6. Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece. 7. Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. 8. Vadaskert Child and Adolescent Psychiatry Clinic, Semmelweis University, Budapest, Hungary. 9. Section of Child Neuropsychiatry, Department of Medical and Pediatric Sciences, Catania University, Catania, Italy. 10. Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle, Germany. 11. Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands. 12. Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Verona, Italy. 13. Department of Pediatrics, Landspitalinn University Hospital, Reykjavik, Iceland. 14. Department of Clinical and Health Psychology, Utrecht University & Altrecht Academic Anxiety Outpatient Clinics, Utrecht. 15. Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 16. Clinic of Psychiatry, Social Psychiatry and Psychotherapy, and Institute of Human Genetics, Hannover Medical School, Hannover, Germany. 17. Wilhelm Johansen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. 18. Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 19. Vadaskert Child and Adolescent Psychiatry Clinic, Semmelweis University, Budapest, Hungary. Electronic address: zeynep.tumer@regionh.dk.
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.
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 GTSpatients 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 GTSpatients 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: Nirmal Vadgama; Alan Pittman; Michael Simpson; Niranjanan Nirmalananthan; Robin Murray; Takeo Yoshikawa; Peter De Rijk; Elliott Rees; George Kirov; Deborah Hughes; Tomas Fitzgerald; Mark Kristiansen; Kerra Pearce; Eliza Cerveira; Qihui Zhu; Chengsheng Zhang; Charles Lee; John Hardy; Jamal Nasir Journal: Eur J Hum Genet Date: 2019-03-18 Impact factor: 4.246
Authors: Natalie J Forde; Ahmad S Kanaan; Joanna Widomska; Shanmukha S Padmanabhuni; Ester Nespoli; John Alexander; Juan I Rodriguez Arranz; Siyan Fan; Rayan Houssari; Muhammad S Nawaz; Francesca Rizzo; Luca Pagliaroli; Nuno R Zilhäo; Tamas Aranyi; Csaba Barta; Tobias M Boeckers; Dorret I Boomsma; Wim R Buisman; Jan K Buitelaar; Danielle Cath; Andrea Dietrich; Nicole Driessen; Petros Drineas; Michelle Dunlap; Sarah Gerasch; Jeffrey Glennon; Bastian Hengerer; Odile A van den Heuvel; Cathrine Jespersgaard; Harald E Möller; Kirsten R Müller-Vahl; Thaïra J C Openneer; Geert Poelmans; Petra J W Pouwels; Jeremiah M Scharf; Hreinn Stefansson; Zeynep Tümer; Dick J Veltman; Ysbrand D van der Werf; Pieter J Hoekstra; Andrea Ludolph; Peristera Paschou Journal: Front Neurosci Date: 2016-08-23 Impact factor: 4.677