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

Attention Deficit Disorder with Hyperactivity / epidemiology Autism Spectrum Disorder / genetics Comorbidity Genome-Wide Association Study Humans Impulsive Behavior Obsessive-Compulsive Disorder / epidemiology Tourette Syndrome / epidemiology
ADHD ASD Cross-disorder genetic analysis GWAS meta-analysis OCD Tourette syndrome

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 09 2021
Historique:
received: 09 03 2020
revised: 21 12 2020
accepted: 21 12 2020
pubmed: 15 3 2021
medline: 28 9 2021
entrez: 14 3 2021
Statut: ppublish

Résumé

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. 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). 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. Our work underlines the value of redefining the framework for research across traditional diagnostic categories.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.biopsych.2020.12.028 PMID: 33714545 PMC: PMC9152955
pubmed: 33714545
pii: S0006-3223(21)00038-X
doi: 10.1016/j.biopsych.2020.12.028
pmc: PMC9152955
mid: NIHMS1661062
pii:
doi:

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

317-327

Subventions

Organisme : NIMH NIH HHS
ID : R01 MH101519
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH119243
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105746
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH109536
Pays : United States

Informations de copyright

Published by Elsevier Inc.

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Auteurs

Zhiyu Yang (Z)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana.

Hanrui Wu (H)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana.

Phil H Lee (PH)

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.

Fotis Tsetsos (F)

Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.

Lea K Davis (LK)

Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.

Dongmei Yu (D)

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.

Sang Hong Lee (SH)

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.

Søren Dalsgaard (S)

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.

Jan Haavik (J)

K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.

Csaba Barta (C)

Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.

Tetyana Zayats (T)

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.

Valsamma Eapen (V)

Academic Unit of Child Psychiatry South West Sydney, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.

Naomi R Wray (NR)

Queensland Brain Institute, University of Queensland, Brisbane, Queensland; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland.

Bernie Devlin (B)

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Mark Daly (M)

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.

Benjamin Neale (B)

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.

Anders D Børglum (AD)

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.

James J Crowley (JJ)

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.

Jeremiah Scharf (J)

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.

Carol A Mathews (CA)

Department of Psychiatry, University of Florida, Gainesville, Florida; Department of Genetics Institute, University of Florida, Gainesville, Florida.

Stephen V Faraone (SV)

Departmentof Psychiatry, SUNY Upstate Medical University, Syracuse, New York; Departmentof Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York.

Barbara Franke (B)

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.

Manuel Mattheisen (M)

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.

Jordan W Smoller (JW)

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.

Peristera Paschou (P)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana. Electronic address: ppaschou@purdue.edu.

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles déficitaires de l'attention et du comportement perturbateur › Trouble déficitaire de l'attention avec hyperactivité › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles généralisés du développement de l'enfant › Trouble du spectre autistique › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Comorbidité › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Comportement et mécanismes comportementaux › Comportement › Comportement impulsif › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Troubles mentaux › Troubles anxieux › Trouble obsessionnel compulsif › Investigating Shared Genetic Basis Across...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles des tics › Syndrome de Tourette › Investigating Shared Genetic Basis Across...