Meta-Analysis

. 2025 Apr 1;97(7):743-752.

doi: 10.1016/j.biopsych.2024.07.025. Epub 2024 Oct 9.

Genome-Wide Association Study Meta-Analysis of 9619 Cases With Tic Disorders

Nora I Strom¹, Matthew W Halvorsen², Jakob Grove³, Bergrún Ásbjörnsdóttir⁴, Pétur Luðvígsson⁵, Ólafur Thorarensen⁵, Elles de Schipper⁶, Julia Bäckmann⁶, Per Andrén⁶, Chao Tian⁷; PGC TS Working Group; 23andMe Research Team; Thomas Damm Als⁸, Judith Becker Nissen⁹, Sandra M Meier¹⁰, Jonas Bybjerg-Grauholm¹¹, David M Hougaard¹¹, Thomas Werge¹², Anders D Børglum⁸, David A Hinds⁷, Christian Rück⁶, David Mataix-Cols⁶, Hreinn Stefánsson⁴, Kari Stefansson⁴, James J Crowley², Manuel Mattheisen¹³

Collaborators, Affiliations

Collaborators

Dongmei Yu, Jae Hoon Sul, Fotis Tsetsos, Muhammad S Nawaz, Alden Y Huang, Ivette Zelaya, Cornelia Illmann, Lisa Osiecki, Sabrina M Darrow, Matthew E Hirschtritt, Erica Greenberg, Kirsten R Muller-Vahl, Manfred Stuhrmann, Yves Dion, Guy Rouleau, Harald Aschauer, Mara Stamenkovic, Monika Schlögelhofer, Paul Sandor, Cathy L Barr, Marco Grados, Harvey S Singer, Markus M Nöthen, Johannes Hebebrand, Anke Hinney, Robert A King, Thomas V Fernandez, Csaba Barta, Zsanett Tarnok, Peter Nagy, Christel Depienne, Yulia Worbe, Andreas Hartmann, Cathy L Budman, Renata Rizzo, Gholson J Lyon, William M McMahon, James R Batterson, Danielle C Cath, Irene A Malaty, Michael S Okun, Cheston Berlin, Douglas W Woods, Paul C Lee, Joseph Jankovic, Mary M Robertson, Donald L Gilbert, Lawrence W Brown, Barbara J Coffey, Andrea Dietrich, Pieter J Hoekstra, Samuel Kuperman, Samuel H Zinner, Pétur Luðvigsson, Evald Sæmundsen, Ólafur Thorarensen, Gil Atzmon, Nir Barzilai, Michael Wagner, Rainald Moessner, Roel Ophoff, Carlos N Pato, Michele T Pato, James A Knowles, Joshua L Roffman, Jordan W Smoller, Randy L Buckner, Jeremy A Willsey, Jay A Tischfield, Gary A Heiman, Hreinn Stefansson, Kári Stefansson, Danielle Posthuma, Nancy J Cox, David L Pauls, Nelson B Freimer, Benjamin M Neale, Lea K Davis, Peristera Paschou, Giovanni Coppola, Carol A Mathews, Jeremiah M Scharf, Michelle Agee, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Barry Hicks, Karen E Huber, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Jey C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Elizabeth S Noblin, Carrie A M Northover, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Janie F Shelton, Suyash Shringarpure, Joyce Y Tung, Vladimir Vacic, Xin Wang

Affiliations

¹ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden; Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address: nora.strom@hu-berlin.de.
² Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
³ Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
⁴ deCODE Genetics/Amgen, Reykjavik, Iceland.
⁵ Department of Pediatrics, Landspitali University Hospital, Reykjavik, Iceland.
⁶ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden.
⁷ 23andMe, Inc., Sunnyvale, California.
⁸ Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
⁹ Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Institute of Health, Aarhus University, Aarhus, Denmark.
¹⁰ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
¹¹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Institute of Biological Psychiatry, Mental Health Services Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark; GLOBE Institute, Center for GeoGenetics, University of Copenhagen, Copenhagen, Denmark.
¹³ Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Department of Community Health and Epidemiology & Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: manuel.mattheisen@dal.ca.

PMID: 39389409
PMCID: PMC12036792 (available on 2026-04-01)
DOI: 10.1016/j.biopsych.2024.07.025

Meta-Analysis

Genome-Wide Association Study Meta-Analysis of 9619 Cases With Tic Disorders

Nora I Strom et al. Biol Psychiatry. 2025.

. 2025 Apr 1;97(7):743-752.

doi: 10.1016/j.biopsych.2024.07.025. Epub 2024 Oct 9.

Authors

Collaborators

Dongmei Yu, Jae Hoon Sul, Fotis Tsetsos, Muhammad S Nawaz, Alden Y Huang, Ivette Zelaya, Cornelia Illmann, Lisa Osiecki, Sabrina M Darrow, Matthew E Hirschtritt, Erica Greenberg, Kirsten R Muller-Vahl, Manfred Stuhrmann, Yves Dion, Guy Rouleau, Harald Aschauer, Mara Stamenkovic, Monika Schlögelhofer, Paul Sandor, Cathy L Barr, Marco Grados, Harvey S Singer, Markus M Nöthen, Johannes Hebebrand, Anke Hinney, Robert A King, Thomas V Fernandez, Csaba Barta, Zsanett Tarnok, Peter Nagy, Christel Depienne, Yulia Worbe, Andreas Hartmann, Cathy L Budman, Renata Rizzo, Gholson J Lyon, William M McMahon, James R Batterson, Danielle C Cath, Irene A Malaty, Michael S Okun, Cheston Berlin, Douglas W Woods, Paul C Lee, Joseph Jankovic, Mary M Robertson, Donald L Gilbert, Lawrence W Brown, Barbara J Coffey, Andrea Dietrich, Pieter J Hoekstra, Samuel Kuperman, Samuel H Zinner, Pétur Luðvigsson, Evald Sæmundsen, Ólafur Thorarensen, Gil Atzmon, Nir Barzilai, Michael Wagner, Rainald Moessner, Roel Ophoff, Carlos N Pato, Michele T Pato, James A Knowles, Joshua L Roffman, Jordan W Smoller, Randy L Buckner, Jeremy A Willsey, Jay A Tischfield, Gary A Heiman, Hreinn Stefansson, Kári Stefansson, Danielle Posthuma, Nancy J Cox, David L Pauls, Nelson B Freimer, Benjamin M Neale, Lea K Davis, Peristera Paschou, Giovanni Coppola, Carol A Mathews, Jeremiah M Scharf, Michelle Agee, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Barry Hicks, Karen E Huber, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Jey C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Elizabeth S Noblin, Carrie A M Northover, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Janie F Shelton, Suyash Shringarpure, Joyce Y Tung, Vladimir Vacic, Xin Wang

Affiliations

¹ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden; Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address: nora.strom@hu-berlin.de.
² Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
³ Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
⁴ deCODE Genetics/Amgen, Reykjavik, Iceland.
⁵ Department of Pediatrics, Landspitali University Hospital, Reykjavik, Iceland.
⁶ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden.
⁷ 23andMe, Inc., Sunnyvale, California.
⁸ Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
⁹ Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Institute of Health, Aarhus University, Aarhus, Denmark.
¹⁰ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
¹¹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Institute of Biological Psychiatry, Mental Health Services Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark; GLOBE Institute, Center for GeoGenetics, University of Copenhagen, Copenhagen, Denmark.
¹³ Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Department of Community Health and Epidemiology & Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: manuel.mattheisen@dal.ca.

PMID: 39389409
PMCID: PMC12036792 (available on 2026-04-01)
DOI: 10.1016/j.biopsych.2024.07.025

Erratum in

Erratum.
[No authors listed] [No authors listed] Biol Psychiatry. 2025 Apr 1;97(7):753. doi: 10.1016/j.biopsych.2025.01.017. Biol Psychiatry. 2025. PMID: 40086899 No abstract available.

Abstract

Background: Despite the significant personal and societal burden of tic disorders (TDs), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor, and identifying risk genes could accelerate progress in the field.

Methods: Expanding upon previous sample size limitations, we added 4800 new TD cases and 971,560 controls and conducted a genome-wide association study (GWAS) meta-analysis with 9619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses.

Results: A genome-wide significant hit (rs79244681, p = 2.27 × 10^-8) within MCHR2-AS1 was identified, although it was not replicated. Post-GWAS analyses revealed a 13.8% single nucleotide polymorphism heritability and 3 significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodmann area 9) and 5 brain cell types (excitatory and inhibitory telencephalon neurons, inhibitory diencephalon and mesencephalon neurons, and hindbrain and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p = .0017) and high-confidence neurodevelopmental disorder genes (p = .0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the 2 single nucleotide polymorphisms previously associated with TDs, one (rs2453763) replicated in an independent subsample of our GWAS (p = .00018).

Conclusions: This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TDs.

Keywords: GWAS; Genetic; Genomic; Psychiatric; Tic disorder; Tourette syndrome.

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Conflict of interest statement

All other authors report no biomedical financial interests or potential conflicts of interest.

References

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Genome-Wide Association Study Meta-Analysis of 9619 Cases With Tic Disorders

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Genome-Wide Association Study Meta-Analysis of 9619 Cases With Tic Disorders

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