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.
Keywords
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Article info
Publication history
Published online: September 03, 2015
Accepted:
August 22,
2015
Received in revised form:
August 21,
2015
Received:
January 29,
2015
Identification
Copyright
© 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- What Makes You Tic? A New Lead in Tourette Syndrome GeneticsBiological PsychiatryVol. 79Issue 5
- PreviewGilles de la Tourette syndrome (GTS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics that can range in severity from mild to disabling. Despite accumulated evidence for a substantial genetic contribution to disease risk, gene discovery in GTS has been challenging. Decades of candidate gene association studies initially reporting positive findings have failed to replicate in larger patient cohorts, and genome-wide association studies have yet to generate statistically significant signals.
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