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

Zhiyu Yang; Hanrui Wu; Phil H Lee; Fotis Tsetsos; Lea K Davis; Dongmei Yu; Sang Hong Lee; Søren Dalsgaard; Jan Haavik; Csaba Barta; Tetyana Zayats; Valsamma Eapen; Naomi R Wray; Bernie Devlin; Mark Daly; Benjamin Neale; Anders D Børglum; James J Crowley; Jeremiah Scharf; Carol A Mathews; Stephen V Faraone; Barbara Franke; Manuel Mattheisen; Jordan W Smoller; Peristera Paschou

doi:10.1016/j.biopsych.2020.12.028

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

Biol Psychiatry. 2021 Sep 1;90(5):317-327. doi: 10.1016/j.biopsych.2020.12.028. Epub 2021 Jan 8.

Authors

Zhiyu Yang¹, Hanrui Wu¹, Phil H Lee², Fotis Tsetsos³, Lea K Davis⁴, Dongmei Yu², Sang Hong Lee⁵, Søren Dalsgaard⁶, Jan Haavik⁷, Csaba Barta⁸, Tetyana Zayats⁹, Valsamma Eapen¹⁰, Naomi R Wray¹¹, Bernie Devlin¹², Mark Daly¹³, Benjamin Neale¹⁴, Anders D Børglum¹⁵, James J Crowley¹⁶, Jeremiah Scharf², Carol A Mathews¹⁷, Stephen V Faraone¹⁸, Barbara Franke¹⁹, Manuel Mattheisen²⁰, Jordan W Smoller²¹, Peristera Paschou²²

Affiliations

¹ Department of Biological Sciences, Purdue University, West Lafayette, Indiana.
² Psychiatric and Neurodevelopmental Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
³ Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
⁴ Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵ Queensland Brain Institute, University of Queensland, Brisbane, Queensland; Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, South Australia.
⁶ Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; Department of Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway.
⁷ K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁸ Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
⁹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
¹⁰ Academic Unit of Child Psychiatry South West Sydney, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
¹¹ Queensland Brain Institute, University of Queensland, Brisbane, Queensland; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland.
¹² Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
¹³ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.
¹⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts; Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
¹⁵ Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark; Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
¹⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
¹⁷ Department of Psychiatry, University of Florida, Gainesville, Florida; Department of Genetics Institute, University of Florida, Gainesville, Florida.
¹⁸ Departmentof Psychiatry, SUNY Upstate Medical University, Syracuse, New York; Departmentof Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York.
¹⁹ Department of Human Genetics, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands; Department of Psychiatry, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
²⁰ Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
²¹ Psychiatric and Neurodevelopmental Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.
²² Department of Biological Sciences, Purdue University, West Lafayette, Indiana. Electronic address: ppaschou@purdue.edu.

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 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.

Keywords: ADHD; ASD; Cross-disorder genetic analysis; GWAS meta-analysis; OCD; Tourette syndrome.

Published by Elsevier Inc.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Attention Deficit Disorder with Hyperactivity* / epidemiology
Attention Deficit Disorder with Hyperactivity* / genetics
Autism Spectrum Disorder* / genetics
Comorbidity
Genome-Wide Association Study
Humans
Impulsive Behavior
Obsessive-Compulsive Disorder* / epidemiology
Obsessive-Compulsive Disorder* / genetics
Tourette Syndrome* / epidemiology
Tourette Syndrome* / genetics

Abstract

Publication types

MeSH terms

Grants and funding