Investigating shared genetic basis across Tourette Syndrome and comorbid neurodevelopmental disorders along the impulsivity-compulsivity spectrum

Abstract Background Tourette Syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum with Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Obsessive-Compulsive Disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum. Methods Investigating the shared genetic basis across TS, ADHD, ASD, and OCD we undertake an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genomewide association studies (GWAS) (93,294 individuals, 6,788,510 markers). Results As previously identified, a common unifying factor connects TS-ADHD-ASD, while TS-OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and targeted approach that is guided by genetic correlations, we are able to identify multiple novel hits as well as regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD GWAS SNP-based and gene-based meta-analysis, we uncover 13 genomewide significant regions that host SNPs with a high posterior probability for association with all three studied disorders (m-value>0.9), 11 of which were not identified in previous cross-disorder analysis. On the other hand, we also identify two additional pleiotropic regions in TS-OCD meta-analysis. Through conditional analysis, we highlight genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue-specificity analysis implicates the hypothalamus-pituitary-adrenal gland axis. Conclusions Our work underlines the value of re-defining the framework for research across traditional diagnostic categories.