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Contribution of copy number variations to education, socioeconomic status and cognition from a genome-wide study of 305,401 subjects

Molecular Psychiatry volume 30, pages 889–898 (2025)Cite this article

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Abstract

Educational attainment (EA), socioeconomic status (SES) and cognition are phenotypically and genetically linked to health outcomes. However, the role of copy number variations (CNVs) in influencing EA/SES/cognition remains unclear. Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31, and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb), and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders. Our findings provide a genome-wide CNV profile for EA/SES/cognition and bridge their connections to health. The expanded candidate CNVs database and the residing genes would be a valuable resource for future studies aimed at uncovering the biological mechanisms underlying cognitive function and related clinical phenotypes.

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Fig. 1: Analysis framework and key findings of this study.
Fig. 2: Genome-wide CNV-level associations for EA/SES/cognition.
Fig. 3: Functional annotation of identified CNV genes.
Fig. 4: Phenome-wide association of EA/SES/cognition-associated CNVs.

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Data availability

Genotype, behavioral and neuroimaging data from the UK Biobank dataset are available at https://biobank.ndph.ox.ac.uk/ by application. The variables used in this study are detailed in Supplementary Table 1. The previously published GWASs of EA/SES/cognition was downloaded from https://www.ebi.ac.uk/gwas/.

Code availability

PennCNV 1.0.5 (https://penncnv.openbioinformatics.org/) was used for CNV calling. PLINK 2.0 (https://www.cog-genomics.org/plink) was used to perform genome-wide CNV-phenotypes analysis and gene-level association analysis. ANNOVAR (https://annovar.openbioinformatics.org/) was used for CNV-gene mapping. STRING (https://www.stringdb.org/) and Metaspace (https://metascape.org) were used for protein-protein interaction network. FUMA (https://fuma.ctglab.nl/) and Metaspace (https://metascape.org) were used to perform gene set enrichment analysis. Cytoscape (https://cytoscape.org/) for calculating importance score. PheWAS 0.99.5-5 package in R version 4.0.3 was used to perform the phenome-wide association study.

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Acknowledgements

This study was conducted under the UK Biobank application ID 19542. We thank the participants and researchers from the UK Biobank. This study was supported by grants from the STI2030-Major Projects (2022ZD0211600), National Natural Science Foundation of China (92249305, 82071201, 81971032), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01), Shanghai Talent Development Funding for The Project (2019074), Research Start-up Fund of Huashan Hospital (2022QD002), Excellence 2025 Talent Cultivation Program at Fudan University (3030277001), and ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University. W.C. was supported by grants from the National Natural Sciences Foundation of China (No. 82071997) and the Shanghai Rising-Star Program (No. 21QA1408700).

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  1. These authors contributed equally: Xin-Rui Wu, Bang-Sheng Wu, Ju-Jiao Kang, Li-Min Chen.

Authors and Affiliations

  1. Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

    Xin-Rui Wu, Bang-Sheng Wu, Li-Min Chen, Yue-Ting Deng, Shi-Dong Chen, Qiang Dong, Wei Cheng & Jin-Tai Yu

  2. Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China

    Ju-Jiao Kang, Jian-Feng Feng & Wei Cheng

  3. Department of Computer Science, University of Warwick, Coventry, CV4 7AL, UK

    Jian-Feng Feng

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Contributions

JTY and WC had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: JTY. Acquisition, analysis, or interpretation of data: XRW, WBS, JJK, LMC, YTD, SDC, QD, JFF, WC and JTY. Drafting of the manuscript: XRW, JJK, WBS, LMC, WC and JTY. Critical revision of the manuscript for important intellectual content: XRW, WBS, JJK, LMC, YTD, SDC, QD, JFF, WC and JTY. Statistical analysis: XRW, BSW and JJK. Obtained funding: JTY. Administrative, technical, or material support: QD, JFF, WC and JTY. All authors read and approved the final manuscript.

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Correspondence to Wei Cheng or Jin-Tai Yu.

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The UK Biobank study was approved by the UK Biobank’s research ethics committee and Human Tissue Authority research tissue bank. The current analysis was approved under the UK Biobank application ID 19542. The ethical approval was from the North West Multi-centre Research Ethics Committee (approval letter dated 17th June 2011, Ref 11/NW/0382). Written informed consent was obtained from all participants.

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Wu, XR., Wu, BS., Kang, JJ. et al. Contribution of copy number variations to education, socioeconomic status and cognition from a genome-wide study of 305,401 subjects. Mol Psychiatry 30, 889–898 (2025). https://doi.org/10.1038/s41380-024-02717-z

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