Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Gilles de la Tourette syndrome (GTS) and other Tic Disorders (TDs) have a substantial genetic component with their heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients, their families, and control samples (n = 278). The model is based on the overrepresentation of coding and non-coding genetic variants in and in the vicinity of genes selected from a set of 84 genes previously indicated as putatively associated with GTS. In the discovery phase, based on a variant burden test between unrelated GTS cases (n = 37) and a database of local allele frequencies 10 genes were selected for the model ( CHADL , DRD2 , MAOA , PCDH10 , HTR2A , SLITRK5 , SORCS3 , KCNQ5 , CDH9, and CHD8 ). Variants in these genes (n = 7654) with a median minor allele frequency in the non-Finnish European population of 0.02 were integrated into an additive classifier. This risk model was then applied to healthy and GTS-affected individuals from 23 families and 100 unrelated healthy samples from the Polish population (AUC-ROC=0.62, p=0.02). Application of the oligogenic model to a group of patients with other tic disorders revealed a continuous increase of the oligogenic score with healthy individuals with the lowest mean, then patients with other tic disorders, then GTS patients, and finally with severe GTS cases with the highest oligogenic score. Results were also overlapped with Psychiatric Genomics Consortium (PGC) GWAS data and we found no significant overlap between the common variant signal and our oligogenic model (p=0.21). Therefore obtained results were compared with the polygenic risk score built from the PGC GWAS data, which revealed a significant contribution of common variant background in severe GTS cases. Overall, we leveraged WGS data to construct a GTS/TDs risk model based on variants that may cooperatively contribute to the etiology of these disorders. This study provides evidence that typical and severe adult GTS as well as other tic disorders may exist on a single spectrum in terms of their genetic background. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Science Center, Poland (NCN) project UMO-2016/23/B/NZ2/03030 lead by CZ. Computational resources for this research were supplied by PL-Grid Infrastructure. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Ethics Committee of the Medical University of Warsaw (KB/2/2007, KB/53/A/2010, KB/63/A/2018) and The District Medical Chamber in Gdansk (KB-8/19) and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants or their legal representatives gave written informed consent prior to inclusion in the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Datasets generated during the current study are available in the Supplementary Material. The main raw results consist of summary statistics of all genetic variants genotyped during Whole Genome Sequencing and are available in Supplementary Table S1. These summary statistics are provided as individual genotype-phenotype data are not publicly available due to the personal data protection act and the type of consent the study participants gave. All the code used in this project is available in the oligogenic model section in the project GitHub repository.