Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size

Abstract

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. Imaging data was collected from 10 centers worldwide, including 474 subjects with 22q11DS (age=18.2±8.6; 46.9% female) and 315 typically-developing, matched controls (age=18.0±9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d=0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d=−1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

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

“…22q11.2 and 16p11.2 CNVs had large effect sizes on FC that are similar to those previously reported for structural neuroimaging measures, cognition, and behaviour 8,10,11 . In sharp contrast, there is a significant discordance between the severe clinical manifestations observed in idiopathic ASD and SZ, and the small effect-size observed in case-control studies at the FC level.…”

“…CNVs at the proximal 16p11.2 and 22q11.2 genomic loci are among the most frequent large effect-size genomic variants and alter the dosage of 29 and 50 g enes, respectively 6,7 . They confer high risk for ASD (10-fold increase for the 16p11.2 deletion and duplication) 3 , SZ (>10-fold increase for the 22q11.2 deletion and 16p11.2 duplication) 4 , and ADHD [8][9][10][11][12] . Gene dosage (deletions and duplications) affect the same neuroimaging measures in opposite directions.…”

“…Structural alterations of the cingulate, insula, precuneus and superior temporal gyrus overlap with those observed in meta-analytical maps of idiopathic psychiatric conditions including ASD and SZ. 10,11 Large effect-size mutations can shed light on pathways connecting genetic risk to brain endophenotypes, such as functional connectivity (FC). However, few studies have investigated the effect of 'neuropsychiatric' CNVs on FC.…”

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study

“…A previous single site study of 22q11DS and youth at clinical high risk for psychosis reported this directionally opposite pattern as well [24]. This is in contrast to findings for cortical gray matter, in which 22q11DS patients with psychosis showed highly significant overlap with idiopathic schizophrenia, in terms of prominent cortical thinning in fronto-temporal regions [35]. Thus, our findings suggest that patterns of neuroanatomic overlap in 22q11DS-associated vs. idiopathic psychosis markedly differ for gray and WM, and suggest that different WM phenotypes may lead to similar downstream clinical outcomes.…”

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

“…Genetic association studies continue to identify both common and rare variants that impact brain structures at the gross anatomical level. [124][125][126] MRI is suited to measure gross structural traits of intracranial volume and regional phenotypes like hippocampal volume or cortical surface area and thickness. [6][7][8]74,[81][82][83] These phenotypes can be measured in large numbers of living humans at a relatively affordable cost.…”