Mutations associated with neuropsychiatric conditions 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) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.

Lessons Learned From Neuroimaging Studies of Copy Number Variants: A Systematic Review

“…A steadily increasing number of morphometry studies using T1-weighted structural MRI in CNV carriers have highlighted robust and large effects on brain structures that partially overlap with those previously observed in idiopathic psychiatric disorders (21)(22)(23). These J o u r n a l P r e -p r o o f studies were conducted one mutation at a time, thus providing a complex catalogue of brain anatomy patterns linked to different genomic loci.…”

Social isolation, loneliness and all-cause dementia: a longitudinal and imaging-genetic study in the UK Biobank cohort

“…The statistical significance of the variance explained by PLS1 was tested by recomputing PLS using 5000 null t-statistic maps which were obtained by label shuffling for social isolation, and counting the number of times the explained variance was higher than the original observation (denoted as P perm ). 33 As PLS1 was not significant in subcortical regions, the following analyses were limited in cortical regions.…”

Atlas of functional connectivity relationships across rare and common genetic variants, traits, and psychiatric conditions

“…Patients diagnosed with idiopathic SZ, BIP, ASD but not ADHD significantly altered FC compared to controls. For SZ, ADHD, and ASD, profiles were previously published ( 20 ) but we recomputed them for ADHD and SZ after adding individuals. Correlations between new and previously published profiles were 0.70 and 0.95, respectively.…”

“…To investigate the transcriptomic relationship of FC-profiles, we aligned gene expression values in the adult human brain from the AHBA dataset ( 17 ) to the MIST64 brain parcellation ( 47 ), as described in ( 20, 47, 62, 63 ).…”

“…Such approaches offer opportunities to investigate effects of genetic factors on FC irrespective of clinical diagnoses. Deletions and duplications at the 16p11.2 and 22q11.2 loci have been associated with mirror effects on global FC (i.e., average connectivity strength across all regions in the brain)( 20 ). In contrast to diagnostic-first studies, effect-sizes for high-risk neuropsychiatric mutations were of similar magnitude for neuroimaging features and behavioral traits ( 19 ).…”