Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum
Yang, Zhiyu; Wu, Hanrui; Lee, Phil H.; Tsetsos, Fotis; Davis, Lea K.; Yu, Dongmei; Lee, Sang Hong; Dalsgaard, Søren; Haavik, Jan; Barta, Csaba; Zayats, Tetyana; Eapen, Valsamma; Wray, Naomi R.; Devlin, Bernie; Daly, Mark; Neale, Benjamin; Børglum, Anders D.; Crowley, James J.; Scharf, Jeremiah; Mathews, Carol A.; Faraone, Stephen V.; Franke, Barbara; Mattheisen, Manuel; Smoller, Jordan W.; Paschou, Peristera
Journal article, Peer reviewed
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OriginalversjonBiological Psychiatry. 2021, 90 (5), 317-327. 10.1016/j.biopsych.2020.12.028
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 undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers). Results As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and 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 genome-wide association study single nucleotide polymorphism–based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms 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. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD. Conclusions Our work underlines the value of redefining the framework for research across traditional diagnostic categories.