Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 1;182(8):763-778.
doi: 10.1176/appi.ajp.20240445. Epub 2025 Jun 11.

Copy Number Variant Architecture of Child Psychopathology and Cognitive Development in the ABCD Study

Zhiqiang Sha  1 , Kevin Y Sun  1 , Benjamin Jung  1 , Ran Barzilay  1 , Tyler M Moore  1 , Laura Almasy  1 , Jennifer K Forsyth  1 , Smrithi Prem  1 , Michael J Gandal  1 , Jakob Seidlitz  1 , Joseph T Glessner  1 , Aaron F Alexander-Bloch  1
Affiliations

Copy Number Variant Architecture of Child Psychopathology and Cognitive Development in the ABCD Study

Zhiqiang Sha et al. Am J Psychiatry. .

Abstract

Objective: Late childhood is a crucial period for individuals with psychiatric disorders. While common single-nucleotide polymorphisms explain a large proportion of inherited risk, structural variations including copy number variants (CNVs) play a significant role in the genetic architecture of neurodevelopmental disorders. The relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored. The authors conducted a comprehensive exploration of the CNV architecture underlying dimensions of psychopathology and cognitive phenotypes within the Adolescent Brain Cognitive Development (ABCD) Study.

Methods: Using two algorithms for CNV detection, the authors identified duplications and deletions across 11,876 individuals from the ABCD Study. Quality control procedures considered array log R ratio and B allele frequency profiles, CNV size, agreement between the two algorithms, and genomic location of CNVs. CNVs that passed quality control were used to identify regions associated with quantitative measures of broad psychiatric symptom domains and cognitive functioning. Additionally, CNV risk scores, reflecting the aggregated burden of genetic intolerance to inactivation and dosage sensitivity, were calculated to assess cumulative impact on overall and dimensional psychiatric and cognitive phenotypes.

Results: Across 8,564 individuals whose data passed quality control, 4,111 carried 5,760 autosomal CNVs. Although no CNV regions reached significance after strict multiple testing correction was applied, 16 regions were associated with psychopathology and cognitive development at an uncorrected genome-wide significance level. A duplication at 14q11.2 showed the strongest association with attentional psychopathology. Moreover, individuals carrying CNVs previously associated with neurodevelopmental disorders exhibited greater impairment in social functioning and cognitive performance across fluid intelligence, working memory, and processing speed. Notably, higher CNV risk scores were significantly correlated with greater attention problems and cognitive impairment across multiple domains (fluid intelligence, attention, working memory, flexible thinking, and processing speed).

Conclusions: These findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology.

Keywords: Child/Adolescent Psychiatry; Genetics/Genomics; Neurodevelopmental Disorders.

PubMed Disclaimer

Conflict of interest statement

Dr. Barzilay serves on the scientific advisory board of and holds equity in Taliaz Health. Dr. Seidlitz is a director of and holds equity in Centile Bioscience. Dr. Alexander-Bloch has served as a consultant for Octave Bioscience, and he holds equity in and serves on the board of Centile Bioscience. The other authors report no financial relationships with commercial interests.

Update of

References

    1. Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. Lancet Psychiatry. 2017;4:339–346. - PubMed
    1. Bolte S, Neufeld J, Marschik PB, Williams ZJ, Gallagher L, Lai MC. Sex and gender in neurodevelopmental conditions. Nat Rev Neurol 2023;19:136–159. - PMC - PubMed
    1. Parenti I, Rabaneda LG, Schoen H, Novarino G. Neurodevelopmental Disorders: From Genetics to Functional Pathways. Trends Neurosci 2020;43:608–621. - PubMed
    1. Takumi T, Tamada K. CNV biology in neurodevelopmental disorders. Curr Opin Neurobiol 2018;48:183–192. - PubMed
    1. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–573. - PMC - PubMed

LinkOut - more resources