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

Cheng, Muyang, Yin, Yue, Engchuan, Worrawat, Heung, Tracy, International 22q11.2 Brain Behavior Consortium (IBBC), Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862 and van den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254 2026. Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion. Molecular Psychiatry 31 , pp. 4934-4946. 10.1038/s41380-026-03574-8

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Additional Information:	For full list of authors please see https://doi.org/10.1038/s41380-026-03574-8
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	1359-4184
Date of First Compliant Deposit:	11 May 2026
Date of Acceptance:	16 March 2026
Last Modified:	02 Sep 2026 13:22
URI:	https://orca.cardiff.ac.uk/id/eprint/186918

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