Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion

Schizophrenia develops in one in every four individuals with a pathogenic 22q11.2 deletion, yet the genetic modifiers influencing the manifestation of schizophrenia in this high-risk group remain incompletely understood. Here, we identify rare tandem repeat expansions (TREs) as significant contributors to schizophrenia risk in this population. Genome sequencing of 438 unrelated individuals with 22q11.2 deletions revealed a marked enrichment of rare genic TREs among those with schizophrenia, with effect sizes comparable to common polygenic risk. These TREs are disproportionately located in intronic and splice-adjacent regions relative to other genomic regions, with evidence suggesting that they disrupt gene regulation through mechanisms including altered methylation and splicing. Cell-type-specific analyses indicate that TREs are primarily associated with differentially expressed genes in excitatory and inhibitory neurons in the prefrontal cortex. Affected genes, including DLGAP2 and DMPK, are involved in neurodevelopment and synaptic organization. These findings extend the role of TREs as genetic modifiers, providing new insights into the molecular mechanisms underlying schizophrenia in this ultra-high-risk population and into the broader biology of idiopathic schizophrenia.

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Journal
Molecular Psychiatry
Published
2026-04-15
DOI
https://doi.org/10.1038/s41380-026-03574-8
Primary Topic
Congenital heart defects research
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article
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0.00

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article

Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion

Tiffany Busa, Marta Unolt, Massimo Biondi, Bruno Dallapiccola et al.
Molecular Psychiatry
Congenital heart defects research
article

Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion

Tiffany Busa, Marta Unolt, Massimo Biondi, Bruno Dallapiccola, Marco Armando, Claudia Ornstein, Kathryn L. McCabe, Beverly S. Emanuel, Elfi Vergaelen, Wendy R. Kates, Rens Evers, Elizabeth Goldmuntz, C. Silversides, Bernice E. Morrow, Maude Schneider, Antonino Buzzanca, Ryan K. C. Yuen, Kathleen Angkustsiri, Deyou Zheng, Elena Michaelovsky, Kelly Schoch, Michael P. Epstein, Daniella Miller, T. van Amelsvoort, Claudia Vingerhoets, Damián Heine‐Suñer, Fernando García Algas, Gabriela M. Repetto, Rosemarie Fritsch, Tracy Heung, Maria Pontillo, Lijie Shi, Matthew S. Hestand, Erik Boot, Worrawat Engchuan, Carolina Putotto, Abraham Weizman, Ronnie Weinberger, T Wang, Andrea Jin, Jaume Morey-Canyelles, Terrence Blaine Crowley, Ann Swillen, Isabelle Cleynen, Stylianos E. Antonarakis, Stefano Vicari, Anne S. Bassett, Zhengdong Zhang, Yujue Wang, Yue Yin, Nigel Williams, Luis Fernández, Arango Celso, Miri Carmel, Joseph F. Cubells, María Angeles de la Fuente Sanches, Joris R. Vermeesch, Donna McDonald-McGinn, Marianne B.M. van den Bree, Oanh T. Tran, Raquel E. Gur, Stephen Hooper, Ania Fiksinski, Elaine H. Zackai, D. A. van Duin Esther, Leila Kushan-Wells, David Cutler, Jeroen Breckpot, Ehod Mekori, Jhih-Rong Lin, Eva W. C. Chow, Nancy Butcher, Carrie E. Bearden, Alejandra Laorden-Nieto, Doron Gothelf, Bruno Marino, Kieran C. Murphy, Declan G. Murphy, Linda Campbell, H. Richard Johnston, Muyang Cheng, Michael Zwick, Daniel McGinn, Jacob Vorstman, Michael J. Owen, Elemi Breetvelt, Yingjie Zhao, Sixto García-Miñaúr, Christian R. Marshall, Vandana Shashi, Stephan Eliez, M. Cristina Digilio, Guido Lattanzi
article en

Abstract

Schizophrenia develops in one in every four individuals with a pathogenic 22q11.2 deletion, yet the genetic modifiers influencing the manifestation of schizophrenia in this high-risk group remain incompletely understood. Here, we identify rare tandem repeat expansions (TREs) as significant contributors to schizophrenia risk in this population. Genome sequencing of 438 unrelated individuals with 22q11.2 deletions revealed a marked enrichment of rare genic TREs among those with schizophrenia, with effect sizes comparable to common polygenic risk. These TREs are disproportionately located in intronic and splice-adjacent regions relative to other genomic regions, with evidence suggesting that they disrupt gene regulation through mechanisms including altered methylation and splicing. Cell-type-specific analyses indicate that TREs are primarily associated with differentially expressed genes in excitatory and inhibitory neurons in the prefrontal cortex. Affected genes, including DLGAP2 and DMPK, are involved in neurodevelopment and synaptic organization. These findings extend the role of TREs as genetic modifiers, providing new insights into the molecular mechanisms underlying schizophrenia in this ultra-high-risk population and into the broader biology of idiopathic schizophrenia.

Molecular Psychiatry
Universidad de Santiago de Chile (CL), University of North Carolina at Chapel Hill (US), University of Geneva (CH), Albert Einstein College of Medicine (US), University Health Network (CA), Children's Hospital of Philadelphia (US), Universidad del Desarrollo (CL), Centre for Addiction and Mental Health (CA), Royal College of Surgeons in Ireland (IE), Emory University (US), University of California, Los Angeles (US), Tel Aviv University (IL), Duke University (US), University of California, San Francisco (US), King's College London (GB), University of Toronto (CA), SUNY Upstate Medical University (US), Hospital Universitario La Paz (ES), Hospital for Sick Children (CA), Toronto General Hospital (CA), Hospital General Universitario Gregorio Marañón (ES), University Medical Center Utrecht (NL), Maastricht University (NL), Assistance Publique Hôpitaux de Marseille (FR), Neurobehavioral Systems (US), Center for Human Genetics (US), University Hospital of Geneva (CH), Seattle Children's Hospital (US), King's College School (GB), Bambino Gesù Children's Hospital (IT), Health Research Institute of the Balearic Islands (ES), Hospital Clínico de la Universidad de Chile (CL), SickKids Foundation (CA), Edmond and Lily Safra Children's Hospital (IL), Institute for Clinical Evaluative Sciences (CA), Hospital Universitario Son Espases (ES), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Wilhelmina Children's Hospital (NL), Hôpital de la Timone (FR), University of Maryland, College Park (US), Pacific Biosciences (United States) (US), University of Chile (CL), University of Newcastle Australia (AU), Cardiff University (GB), University of Pennsylvania (US), University of California, Davis (US), Sapienza University of Rome (IT), KU Leuven (BE)
Genome Canada, Fondation Brain Canada, Centre for Addiction and Mental Health, Canada Research Chairs, University of Toronto, Hospital for Sick Children, Canadian Institutes of Health Research, National Institute of Mental Health
Good health and well-being
Openalex Percentile: Top 21%
Congenital heart defects research
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