Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort

Birgitte Bertelsen, Hreinn Stefansson, Lars Riff Jensen, Linea Melchior, Nanette Mol Debes, Camilla Groth, Liselotte Skov, Thomas Werge, Iordanis Karagiannidis, Zsanett Tarnok, Csaba Barta, Peter Nagy, Luca Farkas, Karen Brondum-Nielsen, Renata Rizzo, Mariangela Gulisano, Dan Rujescu, Lambertus A. Kiemeney, Sarah Tosato, Muhammad Sulaman NawazAndres Ingason, Unnur Unnsteinsdottir, Stacy Steinberg, Petur Ludvigsson, Kari Stefansson, Andreas Walter Kuss, Peristera Paschou, Danielle Cath, Pieter J. Hoekstra, Kirsten Mueller-Vahl, Manfred Stuhrmann, Asli Silahtaroglu, Rolph Pfundt, Zeynep Tumer*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

32 Citaten (Scopus)


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 x 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.

Originele taal-2English
Pagina's (van-tot)383-391
Aantal pagina's9
TijdschriftBiological Psychiatry
Nummer van het tijdschrift5
StatusPublished - 1-mrt.-2016

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