Preferential effects on cognitive ability of deletions versus duplications across biological functions

The pathogenic copy number variants (CNVs) are detected in 10-15% of patients referred for neurodevelopmental disorders (NDD). They are very rare and affect many genes depent of CNVs length. Moreover, our understanding of biological function linked to NDD and cognitive ability when disrupted by gene dosage stem from a small number of genes included in a few recurrent CNVs. However, previous studies have shown that a large proportion of the coding genome affect cognitive ability when disrupted by CNVs. A systematic analysis of the relationship between, gene dosage, cognitive ability and gene function has not been conducted. We posit that by partitioning the genome based on biological functions, we can gain deeper insights into the biological mechanisms that contribute to cognitive abilities in the context to gene dosage. We aim to estimate effect sizes on cognitive ability of all genes disrupted by any CNVs aggregated on the basis of their biological function. We identified and filtered all CNV >50kb from microarray data using PennCNV and QuantiSNP, in 258,292 individuals from 6 unselected population cohorts. Cognitive ability was measured using different assessments. We partitioned the coding genome with available constraint scores (LOEUF) in partially overlapping Syngo(n=293) and GOterm(n=19,700) categories. We then performed a linear model to estimate the mean effect size of each geneset. Out of the 18,451 coding genes with a LOEUF value, 31% and 55% were fully deleted or duplicated, respectively. We have 16 SynGo and 729 GOterm significant for deletion or duplication with at least 30 carriers and a gene coverage ≥20%.Analyses across SynGO showed the strongest negative effects for deletions and duplications in post- and pre- synaptique genesets respectively. Deletions and duplication effect sizes were negatively correlated. To further investigate potential mirror patterns at the microscopic functional level, we used GO-terms geneset. ReviGo summary based on the largest negative impacts (top 5%) on cognitive ability when deleted, highlighted cardiaque development and neuronal communication pathways. Duplications showed top negative impacts in synaptic maturation and negative regulations of multiple molecular pathways. The same negative correlation was observed between deletion and duplication effect sizes. These mirror patterns of effect sizes between deletions and duplication were also observed for intolerant (LOEUF1) genes separately with stronger negative effect for the most intolerant genes. In this study we provide genetic correlations between the estimates of deletions and duplication aggregated across biological function. This is the first time, we observed a dissociation between the effects of CNVs type on cognitive ability. On average, biological functions that affect cognition most in the context of deletions have smaller effects for duplications and vice versa. This highlight the fact that the same biological functions affected by variants with opposing effects on transcription may show very different effects on cognitive ability. Finally, the constraint score has a negative influence on cognition across various biological functions. These observations offer a new perspective on the genetic architecture of cognitive function in the general population and provide a new avenue to explore in the NDD. We will extend this approach to other traits and psychiatric diagnoses.