Unraveling the impact of genomic variations on cognitive ability across the human cortex: insights from gene expression and copy number variants

Relating behavior to inter-individual genetic variation and changes in transcription across the cortex remains a key question in neuroscience. Genomic deletions and duplications - copy number variants (CNVs) - increase the risk for psychiatric conditions and decrease cognitive ability in the general population. Deletions and duplications fully encompassing one or more genes, invariably lead to opposing effects on transcription in the brain. Whether the effects of CNVs on cognition are linked to where gene expression is altered in the cortex has not been investigated. We aim to map the effects of CNVs on cognitive ability across the human cortex. To achieve this, we analyzed measures of cognitive abilities and CNV calls (> 50 kilobases) in over 259,000 individuals from unselected populations (CARTaGEN, Generation Scotland, IMAGEN, Lothian Birth Cohort, Saguenay Youth Study, and UK Biobank). We i) assigned 16,000 coding genes to 180 cortical brain regions of the Glasser parcellation based on their preferential expression across the human cortex of healthy adults provided by the Allen Human Brain Atlas (AHBA); and ii) performed a brain-based GWAS: 180 burden association analyses (linear models) estimating the mean effect size on cognitive ability of genes altered by CNVs for each of the cortical regions, for deletions and duplications separately. Results show that when affected by CNVs, 71% and 62% of the 180 cortical brain region gene sets were associated with a significant (Bonferroni) decrease in cognitive ability for deletions and duplications respectively. The spatial pattern of effect sizes was negatively correlated between deletions and duplications. Both maps also correlated with the well-established cytoarchitectural and functional gradient of the human cortex. The largest effect sizes for deletions and duplications were observed for gene sets preferentially expressed in sensorimotor and association regions respectively. Stratifying genes based on intolerance to loss of function (3 non-overlapping groups) resulted in larger effect sizes for intolerant compared to tolerant genes. However, the same significant anticorrelated deletion-duplication patterns were observed across all 3 groups, demonstrating that this cortical gradient of effect size is orthogonal to dosage-sensitivity scores. Results were also robust to stratification across tissue-specificity, cell types, and developmental epochs, and were replicated in an independent gene expression dataset (Human Protein Atlas). We delineate for the first time a novel functional axis across the cortex, which dissociates the effects of deletions and duplications (effectively a decrease or an increase in transcription) on cognitive ability.