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. The imaging data were 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 3 Mb 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.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the article.Micro-deletions or duplications of chromosomal regions are causally involved in a range of developmental brain disorders [1]
The spatial pattern of thicker cortex in 22q11.2 deletion syndrome (22q11DS) resembled that of surface area (SA) reduction, with the exception of thicker cortex in bilateral insula, and thinner cortex relative to controls in bilateral parahippocampal and superior temporal gyri, and left caudal anterior cingulate cortex (Fig. 1a)
The most prominent SA reductions were found bilaterally in the medial occipital and anterior cingulate cortex; superior parietal cortex and rostral middle frontal gyrus were among the lateral regions showing significantly smaller SA in 22q11DS
Summary
Micro-deletions or duplications of chromosomal regions (copy number variants; CNVs) are causally involved in a range of developmental brain disorders [1]. Some studies noted increases in cortical thickness in 22q11DS relative to controls, with focal thinning in the superior temporal gyrus and cingulate cortex, along with global reductions in surface area [8, 13, 14, 17,18,19]. It is not clear, if these patterns are universally found in 22q11DS. In other neurogenetic conditions larger deletions are associated with greater phenotypic severity [20]; yet, to our knowledge, no prior studies have investigated the neuroanatomic effects of variations in 22q11.2 deletion size
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