Mirror effect of genomic deletions and duplications on cognitive ability across the human cerebral cortex

Regulation of gene expression shapes the interaction between brain networks which in turn supports psychological processes such as cognitive ability. How changes in the level of gene expression across the cerebral cortex influence cognitive ability remains unknown. Here, we tackle this by leveraging genomic deletions and duplications - copy number variants (CNVs) that fully encompass one or more genes expressed in the human cortex - which lead to large effects on gene expression levels. We assigned genes to 180 regions of the human cerebral cortex based on their preferential expression across the cortex computed using data from the Allen Human Brain Atlas. We aggregated CNVs in cortical regions, and ran a burden association analysis to compute the mean effect size of genes on general cognitive ability for each of the 180 regions. When affected by CNVs, most of the regional gene-sets were associated with lower cognitive ability. The spatial patterns of effect sizes across the cortex were correlated negatively between deletions and duplications. The largest effect sizes for deletions and duplications were observed for gene-sets with high expression in sensorimotor and association regions, respectively. These two opposing patterns of effect sizes were not influenced by intolerance to loss of function, demonstrating orthogonality to dosage-sensitivity scores. The same mirror patterns were also observed after stratifying genes based on cell types and developmental epoch markers. These results suggest that the effect size of gene dosage on cognitive ability follows a cortical gradient. The same brain region and corresponding gene set may show different effects on cognition depending on whether variants increase or decrease transcription. The latter has major implications for the association of brain networks with phenotypes.