Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry

Abstract

Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age-and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion Ͻ control Ͻ duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion Ͼ control Ͼ duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.

High-dimensional mapping of cognition to the brain using voxel-based morphometry and subcortical shape analysis

“…It is also considered to be part of the cognitive control network and it has been hypothesized that this network might form a pathway by which information in the insula, can affect decision making, and therefore influence information processing speed (Cauda, et al, 2011;Deen, et al, 2011). In line with literature, our shape analysis results indicate that subcortical structures are heterogeneous and consist of functionally diverging sub-regions (de Flores, et al, 2015;Fama and Sullivan, 2015;Lin, et al, 2017;Roshchupkin, et al, 2016c). This is illustrated by, e.g., the caudate nucleus showing that its head and tail differ in their associations with global cognition.…”

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

“…While the same CNV may confer risk for each of these neurodevelopmental disorders, carriers show remarkable phenotypic variability [2][3][4][5]. Magnetic resonance imaging (MRI) can help unravel possible underlying brain consequences associated with carrying these CNVs and provide novel insight into neuropathological mechanisms [2,[6][7][8][9][10].…”

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

“…Deletion and duplication at several genomic loci result in mirror effects across many human traits [42][43][44][45] , including brain connectivity. Haploinsufficiency may define functional connectivity dimensions that represent building blocks contributing to idiopathic psychiatric conditions.…”