Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics

Abstract

22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = -1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants.

Keywords: DGCR8; copy number variant; cortical thickness; gene expression; surface area.

Figure 1

Variation across 34 left hemisphere cortical regions in: A) Z-score surface area deviance (ΔSA) severity in 22q11DS patients relative to controls (higher Z-score indicates region with greater reduction in SA in 22q11DS); B) DGCR8 expression; C) AIFM3 expression; D) Z-score cortical thickness deviance (ΔCT) severity in 22q11DS relative to controls (higher Z-score indicates region with greater increase in CT in 22q11DS); and E) P2RX6 expression. Expression of DGCR8 and AIFM3 were significantly associated with ΔSA in 22q11DS and expression of P2RX6 was significantly associated with ΔCT in 22q11DS.

Figure 2

Characterization of 6804 unique gene targets of 59 miRNAs down-regulated in mouse cortex due to DGCR8 deficiency. A) Top five significantly enriched biological process, molecular function, and cellular component GO terms; B) enrichment for specific developmental periods and brain regions; and C) enrichment for specific CNS cell types, defined at varying specificity indices using the Specific Expression Analysis tool (Dougherty et al. 2010). Varying specificity thresholds in (B) and (C) are represented by the hexagon ring layers going from the least specific gene-lists (outer hexagons) to the most specific gene-lists (center), with hexagons scaled to the size of the gene-lists. BH-corrected Fisher’s Exact p-values are plotted for each specificity threshold by color.