P.3.019 - The impact of 1q21.1 copy number variant on brain anatomy

Abstract

Copy number variants (CNVs) at the 1q21.1 locus are associated with autism, schizophrenia and other neurodevelopmental disorders, with significant variance in the severity of specific traits. 1q21.1 deletion carriers have been associated more with schizophrenia than duplications and duplication carriers have been associated more with autism spectrum disorders. Interestingly deletions and duplications of the 1q21.1 CNV show a gene dosage effect, or opposite phenotype, regarding head size: were deletions carriers are microcephalic and duplications carriers are macrocephalic [1]. Aim So far only the clinical phenotype of the 1q21.1 CNV has been described, but no study has investigated the impact of the 1q21.1 CNV on the brain [1], [2], [3] and [4]. The aim of this study is to investigate the gene dosage effect on brain anatomy of 1q21.1 carriers by exploring anatomical brain differences between deletion and duplications carriers and by comparing them with controls. Methods Data sample included structural T1 MPRAGE images coming from Europe and United States. Subjects included had the recurrent CNV at the 1q21.1 locus between breakpoint BP2 and BP4 (Class II) or BP3 and BP3 (Class I). In the analysis we included a total of 22 deletion carriers, 17 duplications carriers and 223 controls. The data distribution, as well as the population description, is available in table 1. Neuroimaging data were preprocessed and analyzed with SPM12 running under MATLAB R2015b. For segmentation of T1 weighted images into tissue classes we used a New Tissue Probability map with increased sensitivity for basal ganglia structures. The statistical design was built in the General Linear Model framework as a multiple regression corrected for age, age squared, gender, total intracranial volume and gray matter volume. Results Both cohorts (Europe and US) display a similar phenotype regarding in IQ differences between carriers compared to controls and also a similar gene dosage effect on head circumference. MRI data from the two cohorts were merged into a single statistical analysis. MRI comparison between deletions and duplications shows gene dosage effect on gray matter volume. Deletion carriers show an increase in gray matter volume in bilateral hippocampus and parahippocampal gyrus, while duplications carriers show an increase in the middle frontal gyrus and in the cingulated. Conclusions Our results suggest that differential expression of the same genes can affect different brain regions. Although additional work is required in order to understand if these changes correlate with specific cognitive mechanisms, behaviour or clinical symptoms. In addition our findings are consistent with the general patterns of grey matter impairment identified in psychiatric disorders [5]. The final objective of this project is to continue the investigation by increasing the sample size for the 1q21.1 CV and by adding other CNVs, for example the 16p11.2 CNV, to the comparison in order to increase our understanding of the impact of genetic risk factor on brain structure.