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

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• 作者：Birgitte Bertelsen^a ; Hreinn Stefá ; nsson^b ; Lars Riff Jensen^c ; Linea Melchior^a ; Nanette Mol Debes^d ; Camilla Groth^d ; Liselotte Skov^d ; Thomas Werge^e ; ^f ; ^g ; Iordanis Karagiannidis^h ; Zsanett Tarnok^a ; Csaba Barta^j ; Peter Nagyⁱ ; Luca Farkasⁱ ; Karen Brø ; ndum-Nielsen^a ; Renata Rizzo^k ; Mariangela Gulisano^k ; Dan Rujescu^l ; Lambertus A. Kiemeney^m ; Sarah Tosatoⁿ ; Muhammad Sulaman Nawaz^b ; Andres Ingason^b ; Unnur Unnsteinsdottir^b ; Stacy Steinberg^b ; Pé ; tur Ludvigsson^o ; Kari Stefansson^b ; Andreas Walter Kuss^c ; Peristera Paschou^h ; Danielle Cath^p ; Pieter J. Hoekstra^q ; Kirsten Mü ; ller-Vahl^r ; Manfred Stuhrmann^r ; Asli Silahtaroglu^s ; Rolph Pfundt^t ; Zeynep Tü ; merⁱ ; ^{zeynep.tumer@regionh.dk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AADAC ; Association study ; CNV ; Copy number variation ; Gilles de la Tourette syndrome ; Neuropsychiatric disorder
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：79
• 期：5
• 页码：383-391
• 全文大小：1032 K

文摘

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.