Recurrent copy number variants and psychiatric outcomes in the context of polygenic scores

Vaez, Morteza, Montalbano, Simone, Waples, Ryan, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412 and van den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254 2026. Recurrent copy number variants and psychiatric outcomes in the context of polygenic scores. JAMA Psychiatry 83 (8) , pp. 827-836. 10.1001/jamapsychiatry.2026.1064

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Abstract

Importance Although both recurrent copy number variants (rCNVs) and polygenic scores (PGSs) impart risk for psychiatric disorders, it remains unclear how they contribute jointly to this risk. Objective To estimate and compare absolute risk of psychiatric disorders associated with rCNVs and PGSs, independently and jointly. Design, Setting, and Participants This genetic association study applied data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark (1981-2008) and followed up until 2015, including all individuals with a hospital diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia spectrum disorder (SSD), or major depressive disorder (MDD), and a subcohort randomly drawn from the source population. Data were analyzed from September 2023 to May 2025. Exposures Carrier status was determined at 27 autosomal rCNV loci and PGSs for psychiatric (and other) outcomes from neonatal blood samples genotyped on microarrays and summary statistics from published association studies. Main Outcomes and Measures Absolute risks were estimated for ADHD, ASD, MDD, and SSD during follow-up using a weighted survival analysis framework, and joint effects of rCNV carriage and PGSs were assessed by fitting generalized linear models. Results In 94 276 unrelated European-ancestry individuals (mean [SD] age at follow-up, 21.9 [7.0] years; 50 653 male [53.7%]), rCNV carriage was associated with increased risk of ASD, ADHD, and SSD but not MDD (β = 0.33; 95% CI, 0.27-0.39; β = 0.29; 95% CI, 0.23-0.35; β = 0.25; 95% CI, 0.17-0.33; and β = 0.04; 95% CI, −0.03 to 0.11, respectively); each PGS was positively associated with risk of the corresponding disorder (β = 0.14; 95% CI, 0.12-0.16; β = 0.28; 95% CI, 0.26-0.30; β = 0.28; 95% CI, 0.26-0.30; and β = 0.38; 95% CI, 0.36-0.40, respectively). PGSs identified more individuals than rCNV carriage at comparable levels of absolute risk, except for ASD. A negative interaction was observed between 16p13.11 duplication and ADHD-PGS on ADHD risk (β = −0.51; 95% CI, −0.86 to −0.16), and there was a trend toward negative rCNV-PGS interaction coefficients across aggregated rCNV groups and each of the 9 most common rCNVs (27 of 39 tests, P binomial = .01). Conclusions and Relevance Findings of this genetic association study highlight the complementary value of rCNVs and PGSs for risk assessment in psychiatric disorders, with indications that PGSs can stratify risk among medium- and high-impact rCNV carriers and rCNV-associated risk may, in some instances, be attenuated among individuals with low PGSs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Additional Information:	For full list of authors please see https://doi.org/10.1001/jamapsychiatry.2026.1064
Publisher:	American Medical Association
ISSN:	2168-622X
Date of First Compliant Deposit:	1 June 2026
Date of Acceptance:	5 March 2026
Last Modified:	02 Sep 2026 10:34
URI:	https://orca.cardiff.ac.uk/id/eprint/187349

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