Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Abstract

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) networks remains unclear.We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify major dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level, and their effect-sizes were twice as large as those of idiopathic conditions. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD.Individuals with higher similarity to deletion FC-signatures exhibited worse behavioral and cognitive symptoms. These seemingly distinct neuropsychiatric mutations showed similar gene co-expression patterns and converged on FC dimensions, that may represent mechanistic building blocks shared across idiopathic conditions.

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

“…In line with these observations, cross-psychiatric diagnoses studies have delineated FC dimensions very similar to those associated with haploinsufficiency and involving the somatosensory motor network, DMN, thalamus and subcortical structures (21) . This is consistent with our current and previous findings showing that the FC patterns shared between CNVs and IPC were correlated to IQ and SRS (9) .…”

“…Manuscript : The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs with our current and previous findings showing that the FC patterns shared between CNVs and IPC were correlated to IQ and SRS (9) .…”

“…Functional connectivity (FC) studies have provided critical insight into the architecture of brain networks involved in neuropsychiatric disorders (NPs), but only a few studies have investigated networks modulated by CNVs (7–9) . These large effect-size mutations can shed light on pathways connecting genetic risk to brain endophenotypes, such as FC.…”

The General Impact of Haploinsufficiency on Brain Connectivity Underlies the Pleiotropic Effect of Neuropsychiatric CNVS

“…Twelve recurrent CNVs have been individually associated with autism spectrum disorder (ASD) (3) , eight with schizophrenia (SZ) (4) , and eight with attention deficit hyperactivity disorder (ADHD) (5) but studies have shown that ultra-rare CNVs at many more genomic are also associated with these conditions (4,6) . Functional connectivity (FC) studies have provided critical insight into the architecture of brain networks involved in neuropsychiatric disorders (NPs), but only a few studies have investigated networks modulated by CNVs (7)(8)(9) . These large effect-size mutations can shed light on pathways connecting genetic risk to brain endophenotypes, such as FC.…”

Resting-state functional connectivity and psychopathology in Klinefelter syndrome (47, XXY)

“…In contrast to several genetically defined neuropsychiatric disorders that are less common than XXY syndrome [e.g. 22q11.2 deletions [12][13][14][15], 16p11.2 copy number variations [13,16], Fragile X disorder [17]], we still lack a brain-wide study of resting-state functional connectivity (rsFC) in XXY syndrome. Our study seeks to address this gap in knowledge with two main considerations in mind.…”