Laboratory of Genome Variation and Genetic Epidemiology

Paschou-Lab Data Share

Study: Targeted re-sequencing approach of candidate genes implicates rare potentially functional variants in Tourette Syndrome etiology. Frontiers in Neuroscience, Section on Child and Adolescent Psychiatry, 2016

Contributors: John Alexander, Hera Potamianou, Jinchuan Xing, Li Deng, Iordanis Karagiannidis, Fotis Tsetsos, Petros Drineas, Zsanett Tarnok, Renata Rizzo, Tomasz Wolanczyk, Luca Farkas, Peter Nagy, Urszula Szymanska, Christos Androutsos, Vaia Tsironi, Anastasia Koumoula, Csaba Barta, TSGeneSEE, Paul Sandor, Cathy L. Barr, Jay Tischfield, Peristera Paschou, Gary A. Heiman and Marianthi Georgitsi.

Dataset access: Available BAM files for 382 TS individuals. Please contact John Alexander (jalexand AT for data access.


Abstract: Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four candidate genes for TS (HDC, SLITRK1, BTBD9 and SLC6A4) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST. We prioritized variants using Variant ranker and validated five rare variants via Sanger sequencing in HDC and SLITRK1, all of which are predicted to be deleterious. Intriguingly, one of the identified variants is in linkage disequilibrium with a variant that is included among the top hits of a genome-wide association study tolerance to citalopram treatment, an antidepressant drug with off-label use also in obsessive compulsive disorder. Our findings provide additional evidence for the implication of these two genes in TS susceptibility and the possible role of these proteins in the pathobiology of TS should be revisited.

Study subjects: A total of 382 individuals with TS were included in the study. The subjects represent affected cases from family trios who had been previously recruited within The Tourette Syndrome Genetics—Southern and Eastern Europe Initiative (TSGeneSEE) and originated from Hungary (n=117), Italy (n=95), Poland (n=68), Greece (n=17) and Albania (n=8). In addition, 77 TS cases originating from Canada were also available. The majority of these individuals have been described previously (Karagiannidis et al., 2013).

Assessment was performed by on-site clinicians using the tools provided by the TS Association International Consortium for Genetics (TSAICG, 2007). TS was ascertained according to DSM-IV-TR criteria for Italy, Hungary, Albania and Greece, and DSM-IV for Poland. For Canadian samples, TS was ascertained using DSM-III-R criteria. Differences between DSM-III-R, DSM-IV and DSM-IV-TR are minimal; the upper age limit of onset is 18 in DSM-IV (and DSM-IV-TR) and 21 in DSM-III-R, and the ‘marked distress’ criterion, possibly pointing to more severe cases, only appears in DSM-IV (applied only to the Polish cases) (Cath et al., 2011).

For all samples, collection was approved by local Ethics Boards and informed consent was taken from all participating individuals or their parents.

Platform: Illumina MiSeq V3


We are indebted to the TS individuals and their families for accepting to participate in the studies of the genetic basis of TS. This study was made possible thanks to the collaborative efforts of Tourette Syndrome Genetics—Southern and Eastern Europe Initiative (TSGeneSEE) and COST Action BM905: European Network for the Study of GTS (EUNETGTS). This project was financed by FP7-316 People-2012-ITN, project: TS-EUROTRAIN, grant number 316978, and grants from the National Institute of Mental Health [R01MH092293; U24MH068457] and the Human Genetics Institute of New Jersey. The collection of Canadian families for this study was supported by grants from The Tourette Syndrome Association of America, N.I.H. grant MS40024-01, the Ontario Mental Health Foundation, and The Tourette Syndrome Foundation of Canada.