Investigation of SNP rs2060546 Immediately Upstream to NTN4 in a Danish Gilles de la Tourette Syndrome Cohort

abstract: ...Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC , and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 ( NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; p -value = 5.8 10-7] thus warranting further investigations. As NTN4 is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins of SLIT and WNT genes guiding the growth cone toward its target, it is an attractive candidate susceptibility gene for GTS. In this study we attempted to replicate the association of rs2060546 with GTS by genotyping a Danish cohort of 240 GTS patients and 1006 healthy controls. Our results did not reveal an association (OR = 1.363; p -value = 0.3329) in the Danish cohort alone, which may be due to the small sample size. However, a meta-analysis including the present cohort and a total of 1316 GTS patients and 5023 controls from the GTS GWAS Replication Initiative (GGRI) and the first GTS-GWAS yielded a significant signal (OR = 3.74; p -value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of NTN4 in GTS etiology, suggesting that further studies in even larger samples and functional studies are warranted to investigate the role of this region in GTS pathogenesis.

...Front Neurosci Front Neurosci Front. Neurosci. Frontiers in Neuroscience 1662-4548 1662-453X Frontiers Media S.A. 27920664 5118467 10.3389/fnins.2016.00531 Neuroscience Original Research Investigation of SNP rs2060546 Immediately Upstream to NTN4 in a Danish Gilles de la Tourette Syndrome Cohort Padmanabhuni Shanmukha S. 1 Houssari Rayan 2 Esserlind Ann-Louise 3 Olesen Jes 3 Werge Thomas M. 4 Hansen Thomas F. 4 Bertelsen Birgitte 2 Tsetsos Fotis 1 Paschou Peristera 1 5 Tmer Zeynep 2 * 1 Department of Molecular Biology and Genetics, Democritus University of Thrace Alexandroupoli, Greece 2 Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark 3 Danish Headache Center and Department of Neurology, Faculty of Health Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark 4 Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital Roskilde, Denmark 5 Department of Biological Sciences, Purdue University West Lafayette, IN, USA Edited by: John Vijay Sagar Kommu, National Institute of Mental Health and Neurosciences, India Reviewed by: Munis Dundar, Erciyes University, Turkey; Suhash Chakraborty, Hindustan Aeronautics Limited Hospital, India *Correspondence: Zeynep Tmer zeynep.tumer@region.dk This article was submitted to Child and Adolescent Psychiatry, a section of the journal Frontiers in Neuroscience 22 11 2016 2016 10 531 04 4 2016 31 10 2016 Copyright 2016 Padmanabhuni, Houssari, Esserlind, Olesen, Werge, Hansen, Bertelsen, Tsetsos, Paschou and Tmer. 2016 Padmanabhuni, Houssari, Esserlind, Olesen, Werge, Hansen, Bertelsen, Tsetsos, Paschou and Tmer This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC , and IMMP2L have been tentatively associated with GTS (in a small number of

... abnormalities have probed new candidate regions containing susceptible genes such as Slit- and Ntrk-Like Family, Member 1 ( SLITRK1 MIM 609678), Neuroligin 4 ( NLGN4 MIM 300427) and Contactin-Associated Protein-Like2 ( CNTNAP2 MIM 604569) (Verkerk et al., 2003 ; Abelson et al., 2005 ; Lawson-Yuen et al., 2008 ; Patel et al., 2011 ). Specific CNV analyses have resulted in the identification of several other candidate genes, including Arylacetamide Deacetylase ( AADAC MIM 600338), Collagen, Type VIII, Alpha-1

... 23989977 Bertelsen B. Melchior L. Jensen L. R. Groth C. Glenthj B. Rizzo R. . ( 2014 ). Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome . Eur. J. Hum. Genet. 22 , 1283 1289 . 10.1038/ejhg.2014.24 24549057 Bertelsen B. Stefnsson H. Riff Jensen L. Melchior L. Mol Debes N. Groth C. . ( 2015 ). Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort . Biol. Psychiatry 79 , 383 391 . 10.1016/j.biopsych

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Gene: AADAC - arylacetamide deacetylase - (NCBI)

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