Elsevier

Biological Psychiatry

Volume 88, Issue 3, 1 August 2020, Pages 260-272
Biological Psychiatry

Archival Report
Reciprocal Copy Number Variations at 22q11.2 Produce Distinct and Convergent Neurobehavioral Impairments Relevant for Schizophrenia and Autism Spectrum Disorder

https://doi.org/10.1016/j.biopsych.2019.12.028Get rights and content

Abstract

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.

Section snippets

Participants

The sample consisted of 226 individuals: 106 with molecularly confirmed 22q11.2 deletions (52 male and 54 female subjects), 38 with confirmed 22q11.2 duplications (22 male and 16 female subjects), and 82 demographically matched, typically developing, healthy control subjects (42 male and 40 female subjects; see Table 1 for participant demographics). Patients were ascertained as part of an ongoing longitudinal study at the University of California at Los Angeles and from local medical or

22q11.2 CNVs Produce Convergent Phenotypes Relevant for ID and ASD but Divergent Psychosis-Relevant Phenotypes

At q < .05, 22q11.2 deletion carriers exhibited the lowest full-scale IQ, healthy control participants displayed the highest IQ, while duplication carriers were intermediate (deletion < duplication < control; see Figure 1, Table 3). The same pattern remained when full-scale IQ was broken down into its constituent parts, verbal and nonverbal IQ. Regarding specific cognitive domains, deletion and duplication carriers exhibited significant impairments in working memory, verbal memory, and

Discussion

This study revealed several novel findings regarding the impact of 22q11.2 CNVs on neurobehavioral function, in that they 1) produce comparable impairments in traits relevant for ASD and intellectual functioning but differential impairments in psychosis-related traits; 2) comprise distinct differences in ASD profile at the subdomain level; and 3) lack the normative relationships between processing speed and CT in higher-order brain regions.

Notably, these reciprocal CNVs conferred broad hits

Acknowledgments and Disclosures

This work was supported by National Institute of Mental Health Grant Nos. RO1 MH085953 (to CEB) and U01MH101719 (to CEB); Neurobehavioral Genetics Predoctoral Training Grant (5T32MH073526 [to AL]); and the Simons Foundation (SFARI Explorer Award [to CEB]).

The authors report no biomedical financial interests or potential conflicts of interest.

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