Background

22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported.

Methods

We profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically matched healthy control subjects. To determine whether brain-behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains.

Results

Cognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD subdomains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally measured positive and negative symptoms were elevated in deletion carriers. Finally, healthy control subjects showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups.

Conclusions

22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability.

Background

Prader Willi Syndrome (PWS) is a genetic disorder caused by the absence of expression of the paternal copies of maternally imprinted gene(s) located at 15q11-q13. While the physical and medical characteristics of PWS, including short stature, hyperphagia and endocrine dysfunction are well-characterized, systematic investigation of the long-recognized psychiatric manifestations has been recent.

Methods

Here, we report on the first remote (web-based) assessment of neurobehavioral traits, including psychosis-risk symptoms (Prodromal Questionnaire-Brief Version; PQ-B) and sleep behaviors (Pittsburgh Sleep Quality Index), in a cohort of 128 participants with PWS, of whom 48% had a paternal deletion, 36% uniparental disomy, 2.4% an imprinting mutation and 13% unknown mutation (mean age 19.3 years ± 8.4; 53.9% female). We aimed to identify the most informative variables that contribute to psychosis-risk symptoms. Multiple domains of cognition (accuracy and speed) were also assessed in a subset of PWS participants (n = 39) using the Penn Computerized Neurocognitive Battery (Penn-CNB).

Results

Individuals with PWS reported a range of psychosis-risk symptoms, with over half reporting cognitive disorganization (63.1%) and about one third reporting unusual beliefs (38.6%) and/or suspiciousness (33.3%). Subjectively-reported sleep quality, nap frequency, sleep duration, sleep disturbance, and daytime dysfunction were significant predictors of psychosis-risk symptom frequency and severity (all p's < 0.029). Sleep disturbance ratings were the strongest predictors of psychosis-risk symptoms. Regarding cognition, individuals with PWS showed the most prominent deficits in accuracy on measures of social cognition involving faces, namely Face Memory, Age Differentiation and Emotion Recognition, and greatest slowing on measures of Attention and Emotion Recognition. However, there were no significant differences in psychosis-risk symptoms or cognitive performance as a function of PWS genetic subtype.

Conclusions

PWS is associated with a high prevalence of distressing psychosis-risk symptoms, which are associated with sleep disturbance. Findings indicate that self/parent-reported neurobehavioral symptoms and cognition can be assessed remotely in individuals with PWS, which has implications for future large-scale investigations of rare neurogenetic disorders.

The Asian wood-boring beetle Anoplophora chinensis (Forster) (Coleoptera: Cerambycidae) is an important pest of hardwood trees in its native range, and has serious potential to invade other areas of the world through worldwide commerce in woody plants and wood products. This species already has been intercepted in North America, and is the subject of ongoing eradication efforts in several countries in Europe. Attractants such as pheromones would be immediately useful as baits in traps for its detection. Because long-range pheromones are frequently conserved among closely related species of cerambycids, we evaluated two components of the volatile pheromone produced by males of the congener A. glabripennis (Motschulsky), 4-(n-heptyloxy)butan-1-ol and 4-(n-heptyloxy)butanal, as potential pheromones of A. chinensis. Both compounds subsequently were detected in headspace volatiles from male A. chinensis, but not in volatiles from females. Only 4-(n-heptyloxy)butanol elicited responses from beetle antennae in coupled gas chromatography-electroantennogram analyses, and this compound attracted adult A. chinensis of both sexes in field bioassays. These data suggest that 4-(n-heptyloxy)butan-1-ol is an important component of the male-produced attractant pheromone of A. chinensis, which should find immediate use in quarantine monitoring for this pest.

Background

Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1.

Methods

BOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM.

Results

Relative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls.

Conclusions

Dysfunctional engagement of WM circuitry, and aberrant functional connectivity of 'task-negative' regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder.

The longhorned beetle Aromia bungii (Coleoptera: Cerambycidae) is a major pest of stone fruit trees in the genus Prunus, including cherries, apricots, and peaches. Its native range includes China, Korea, Mongolia, and eastern Russia, but it has recently invaded and become established in several countries in Europe, and Japan, and it has been intercepted in shipments coming into North America and Australia. Here, we report the identification of its male-produced aggregation pheromone as the novel compound (E)-2-cis-6,7-epoxynonenal. In field trials in its native range in China, and in recently invaded areas of Japan, the pheromone attracted both sexes of the beetle. Thus, the pheromone should find immediate use in worldwide quarantine surveillance efforts to detect the beetle in incoming shipments. The pheromone will also be a crucial tool in ongoing efforts to eradicate the beetle from regions of the world that it has already invaded.

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 < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > 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.SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.

Pendrin is a Cl-/HCO3- exchanger expressed in the apical regions of renal intercalated cells. Following pendrin gene ablation, blood pressure falls, in part, from reduced renal NaCl absorption. We asked if pendrin is expressed in vascular tissue and if the lower blood pressure observed in pendrin null mice is accompanied by reduced vascular reactivity. Thus, the contractile responses to KCl and phenylephrine (PE) were examined in isometrically mounted thoracic aortas from wild-type and pendrin null mice. Although pendrin expression was not detected in the aorta, pendrin gene ablation changed contractile protein abundance and increased the maximal contractile response to PE when normalized to cross sectional area (CSA). However, the contractile sensitivity to this agent was unchanged. The increase in contractile force/cross sectional area observed in pendrin null mice was due to reduced cross sectional area of the aorta and not from increased contractile force per vessel. The pendrin-dependent increase in maximal contractile response was endothelium- and nitric oxide-independent and did not occur from changes in Ca2+ sensitivity or chronic changes in catecholamine production. However, application of 100 nM angiotensin II increased force/CSA more in aortas from pendrin null than from wild type mice. Moreover, angiotensin type 1 receptor inhibitor (candesartan) treatment in vivo eliminated the pendrin-dependent changes contractile protein abundance and changes in the contractile force/cross sectional area in response to PE. In conclusion, pendrin gene ablation increases aorta contractile force per cross sectional area in response to angiotensin II and PE due to stimulation of angiotensin type 1 receptor-dependent signaling. The angiotensin type 1 receptor-dependent increase in vascular reactivity may mitigate the fall in blood pressure observed with pendrin gene ablation.

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.

Objective

22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group.

Methods

Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female).

Results

Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder.

Conclusions

In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

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.