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Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum

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  • Zhiyu Yang, Purdue University
  • ,
  • Hanrui Wu, Purdue University
  • ,
  • Phil H Lee, Massachusetts General Hospital , Harvard University
  • ,
  • Fotis Tsetsos, Democritus University of Thrace
  • ,
  • Lea K Davis, Vanderbilt University Medical Center
  • ,
  • Dongmei Yu, Massachusetts General Hospital , Harvard University
  • ,
  • Sang Hong Lee, University of Queensland, University of South Australia
  • ,
  • Søren Dalsgaard
  • Jan Haavik, University of Bergen, Haukeland University Hospital
  • ,
  • Csaba Barta, Semmelweis University
  • ,
  • Tetyana Zayats, Massachusetts General Hospital , University of Bergen
  • ,
  • Valsamma Eapen, University of New South Wales
  • ,
  • Naomi R Wray, University of Queensland
  • ,
  • Bernie Devlin, University of Pittsburgh School of Medicine
  • ,
  • Mark Daly, Massachusetts General Hospital , Stanley Center for Psychiatric Research
  • ,
  • Benjamin Neale, Massachusetts General Hospital , Stanley Center for Psychiatric Research, Broad Institute
  • ,
  • Anders D Børglum
  • James J Crowley, University of North Carolina at Chapel Hill
  • ,
  • Jeremiah Scharf, Massachusetts General Hospital , Harvard University
  • ,
  • Carol A Mathews, University of Florida
  • ,
  • Stephen V Faraone, SUNY Upstate Medical University
  • ,
  • Barbara Franke, Radboud University
  • ,
  • Manuel Mattheisen, University of Wuerzburg, Karolinska Institutet
  • ,
  • Jordan W Smoller, Massachusetts General Hospital , Harvard University, Stanley Center for Psychiatric Research
  • ,
  • Peristera Paschou, Purdue University

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.

OriginalsprogEngelsk
TidsskriftBiological Psychiatry
Vol/bind90
Nummer5
Sider (fra-til)317-327
Antal sider11
ISSN0006-3223
DOI
StatusUdgivet - sep. 2021

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