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Reciprocal white matter changes associated with copy number variation at 15q11.2 BP1-BP2: A diffusion tensor imaging study

Silva, Ana I. ORCID:, Ulfarsson, Magnus O., Stefansson, Hreinn, Gustafsson, Omar, Walters, G. Bragi, Linden, David E.J. ORCID:, Wilkinson, Lawrence S. ORCID:, Drakesmith, Mark ORCID:, Owen, Michael J. ORCID:, Hall, Jeremy ORCID: and Stefansson, Kari 2019. Reciprocal white matter changes associated with copy number variation at 15q11.2 BP1-BP2: A diffusion tensor imaging study. Biological Psychiatry 85 (7) , pp. 563-572. 10.1016/j.biopsych.2018.11.004

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Background The 15q11.2 BP1-BP2 cytogenetic region has been associated with learning and motor delays, autism, and schizophrenia. This region includes a gene that codes for the cytoplasmic FMR1 interacting protein 1 (CYFIP1). The CYFIP1 protein is involved in actin cytoskeletal dynamics and interacts with the fragile X mental retardation protein. Absence of fragile X mental retardation protein causes fragile X syndrome. Because abnormal white matter microstructure has been reported in both fragile X syndrome and psychiatric disorders, we looked at the impact of 15q11.2 BP1-BP2 dosage on white matter microstructure. Methods Combining a brain-wide voxel-based approach and a regional-based analysis, we analyzed diffusion tensor imaging data from healthy individuals with the deletion (n = 30), healthy individuals with the reciprocal duplication (n = 27), and IQ-matched control subjects with no large copy number variants (n = 19), recruited from a large genotyped population sample. Results We found global mirror effects (deletion > control > duplication) on fractional anisotropy. The deletion group showed widespread increased fractional anisotropy when compared with duplication. Regional analyses revealed a greater effect size in the posterior limb of the internal capsule and a tendency for decreased fractional anisotropy in duplication. Conclusions These results show a reciprocal effect of 15q11.2 BP1-BP2 on white matter microstructure, suggesting that reciprocal chromosomal imbalances may lead to opposite changes in brain structure. Findings in the deletion overlap with previous white matter differences reported in fragile X syndrome patients, suggesting common pathogenic mechanisms derived from disruptions of cytoplasmic CYFIP1-fragile X mental retardation protein complexes. Our data begin to identify specific components of the 15q11.2 BP1-BP2 phenotype and neurobiological mechanisms of potential relevance to the increased risk for disorder.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Psychology
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article under the terms of the CC-BY license.
Publisher: Elsevier
ISSN: 0006-3223
Funders: Wellcome Trust
Date of First Compliant Deposit: 9 January 2019
Date of Acceptance: 12 November 2018
Last Modified: 22 Apr 2024 18:38

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