The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs

Large effect-size mutations such as copy number variants (CNVs) have the potential to provide key insights into the underlying biological mechanisms linking deleterious genetic variants to brain architecture and neuropsychiatric disorders. To date, the effect of CNVs on functional brain connectivity remains mostly unstudied, and findings are derived from analyses conducted one mutation at a time. The lack of systematic cross-CNV comparisons hinders our understanding of any potential general mechanisms linking CNVs to effects on brain organization. We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, and 4 neutral-effect CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity. The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. We reported architecture similarities between individuals with idiopathic psychiatric conditions and high-risk neuropsychiatric-CNVs, predominantly in the thalamus, the posterior cingulate cortex, and the anterior insula. We identified a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders. We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.