title: Investigation of SNP rs2060546 Immediately Upstream toNTN4in 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 asAADAC, NRXN1, SLITRK1, HDC, andIMMP2Lhave 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. AsNTN4is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins ofSLITandWNTgenes 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 ofNTN4in 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.
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace Alexandroupoli, Greece.
authors.forename: Shanmukha S
authors.initials: SS
authors.lastname: Padmanabhuni
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark.
authors.forename: Rayan
authors.initials: R
authors.lastname: Houssari
authors.affiliation: Danish Headache Center and Department of Neurology, Faculty of Health Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark.
authors.forename: Ann-Louise
authors.initials: AL
authors.lastname: Esserlind
authors.affiliation: Danish Headache Center and Department of Neurology, Faculty of Health Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark.
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
authors.affiliation: Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital Roskilde, Denmark.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Werge
authors.affiliation: Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital Roskilde, Denmark.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Hansen
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Bertelsen
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace Alexandroupoli, Greece.
authors.forename: Fotis
authors.initials: F
authors.lastname: Tsetsos
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of ThraceAlexandroupoli, Greece; Department of Biological Sciences, Purdue UniversityWest Lafayette, IN, USA.
authors.forename: Peristera
authors.initials: P
authors.lastname: Paschou
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
keywords: GTS; Gilles de la Tourette syndrome; NTN4; Netrin-4; SNP; axon guidance; single nucleotide polymorphism