Dissecting The Etiology of Tourette Syndrome Through Large-Scale Genome, Epigenome And Transcriptome Studies and Cross-Disorder Analysis

Abstract

Tourette Syndrome (TS) is a psychiatric disorder of childhood onset, marked by multiple motor and vocal tics and is caused by a complex and as of yet not fully understood genetic background interacting with environmental factors. Interestingly, there is a fluctuation in the severity of symptoms, with tics waxing and waning over time. Furthermore, the phenotype is extremely complex with 90% of patients presenting with additional neuropsychiatric symptomatology, and, notably, there is high comorbidity with other neurodevelopmental disorders such as Obsessive-Compulsive Disorder (OCD), Attention Deficit and Hyperactivity Disorder (ADHD), and Autism Spectrum Disorders leading to the hypothesis of a shared genetic basis. There are multiple large-scale efforts aiming to identify the genetic basis of TS and we are starting to reach an inflection point at which results are starting to become reproducible. Importantly, studies of the epigenome and genome-wide gene-expression patterns are allowing us to uncover additional missing pieces of the puzzle. Here, we present results from two of the largest collaborative efforts for TS: EMTICS (European Multicentre Tics in Children Study) and TS-EUROTRAIN (a Marie Curie Initial Training Network). Besides a genome-wide association study on 1500 patients with TS, we also present the first epigenomewide association study for TS supporting a role for aberrant DNA methylation levels in tic disorders as part of a broader neurodevelopmental dysregulation. We also present the first genome-wide gene expression study based on longitudinal follow-up of 700 TS patients for TS for two years and comparisons at points of tic exacerbation and remission in order to identify genes whose expression patterns correlate with tic fluctuation. The genes implicated by our analysis are enriched in cell-adhesion molecules and related to neurodevelopment but intriguingly, also cancer. Interestingly, several microRNAs and small nucleolar RNAs are found among our top hits. Meta-analysis of TS GWAS with GWAS for ADHD and ASD sheds light into the shared etiology identifying genes that play a role across the spectrum of neurodevelopmental disease. Leveraging power from large-scale collaborative efforts and participation from a multitude of clinical sites around the world we present here an integrative view of current studies aiming to understand the etiology of TS.