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.