ArticleJAMA psychiatry2026
Recurrent Copy Number Variants and Psychiatric Outcomes in the Context of Polygenic Scores.
Article in JAMA psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Potential for Genomics to Help Guide Preventive Strategies in Psychiatry.JAMA psychiatry · 2026Article
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15 authors.
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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.
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