Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

Copy-number variants (CNVs) that increase the risk for neurodevelopmental disorders also affect cognitive ability. However, such CNVs remain challenging to study due to their scarcity, limiting our understanding of gene-dosage-sensitive biological processes linked to cognitive ability. We performed a genome-wide association study (GWAS) in 258,292 individuals, which identified—for the first time—a duplication at 2q12.3 associated with higher cognitive performance. We developed a functional-burden analysis, which tested the association between cognition and CNVs disrupting 6,502 gene sets biologically defined across tissues, cell types, and ontologies. Among those, 864 gene sets were associated with cognition, and effect sizes of deletion and duplication were negatively correlated. The latter suggested that functions across all biological processes were sensitive to either deletions (e.g., subcortical regions, postsynaptic) or duplications (e.g., cerebral cortex, presynaptic). Associations between non-brain tissues and cognition were driven partly by constrained genes, which may shed light on medical comorbidities in neurodevelopmental disorders. [Display omitted] •CNV-GWAS reveals the first positive impact on cognition for the 2q12.3 duplication•The effects of deletions/duplications on cognitive ability are negatively correlated•A new metric, tagDS, defines the gene-dosage-effect specificity of any set of genes•Significant impact of genes expressed in non-brain tissues on cognitive ability Copy-number variants are major contributors to neurodevelopmental disorders and are associated with lower cognition. Huguet et al. identified a duplication increasing cognitive ability. They highlighted that genes of many biological processes had unbalanced gene-dosage sensitivity toward deletions or duplications for both brain and non-brain functions.