Department of Economics and Business Economics

Manuel Mattheisen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Zhiyu Yang, Purdue Univ, Purdue University, Purdue University System, Dept Agron
  • ,
  • Hanrui Wu, Purdue Univ, Purdue University, Purdue University System, Dept Agron
  • ,
  • Phil H Lee, Harvard School of Dental Medicine and Harvard Medical School
  • ,
  • Fotis Tsetsos, Democritus Univ Thrace, Democritus University of Thrace, Dept Med
  • ,
  • Lea K Davis, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • ,
  • Dongmei Yu, Harvard School of Dental Medicine and Harvard Medical School
  • ,
  • Sang Hong Lee, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
  • ,
  • Søren Dalsgaard
  • Jan Haavik, Department of Biology, University of Bergen, Bergen, Norway; Sars International Centre, Uni Research, University of Bergen, Bergen, Norway.
  • ,
  • Csaba Barta, Semmelweis Univ, Semmelweis University, Heart & Vasc Ctr
  • ,
  • Tetyana Zayats, Department of Biology, University of Bergen, Bergen, Norway; Sars International Centre, Uni Research, University of Bergen, Bergen, Norway.
  • ,
  • Valsamma Eapen, Kirby Institute, University of New South Wales Medicine, University of New South Wales
  • ,
  • Naomi R Wray, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
  • ,
  • Bernie Devlin, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • ,
  • Mark Daly, Broad Inst MIT & Harvard, Broad Institute, Harvard University, Massachusetts Institute of Technology (MIT), Stanley Ctr Psychiat Res
  • ,
  • Benjamin Neale, Broad Inst MIT & Harvard, Broad Institute, Harvard University, Massachusetts Institute of Technology (MIT), Stanley Ctr Psychiat Res
  • ,
  • Anders D Børglum
  • James J Crowley, Univ North Carolina Chapel Hill, University of North Carolina, University of North Carolina Chapel Hill, University of North Carolina School of Medicine, Dept Phys & Astron
  • ,
  • Jeremiah Scharf, Harvard School of Dental Medicine and Harvard Medical School
  • ,
  • Carol A Mathews, Univ Florida, Florida State University System, University of Florida, Florida Museum Nat Hist
  • ,
  • Stephen V Faraone, SUNY Upstate Medical University
  • ,
  • Barbara Franke, AU Cognition and Behaviour Lab
  • ,
  • Manuel Mattheisen
  • Jordan W Smoller, Broad Inst MIT & Harvard, Broad Institute, Harvard University, Massachusetts Institute of Technology (MIT), Stanley Ctr Psychiat Res
  • ,
  • Peristera Paschou, Purdue Univ, Purdue University, Purdue University System, Dept Agron

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.

Original languageEnglish
JournalBiological Psychiatry
ISSN0006-3223
DOIs
Publication statusE-pub ahead of print - 8 Jan 2021

See relations at Aarhus University Citationformats

ID: 213691527