Estimating the effect-size of gene dosage on cognitive ability across the coding genome

Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.