Reciprocal White Matter Changes Associated With Copy Number Variation at 15q11.2 BP1-BP2: A Diffusion Tensor Imaging Study

Abstract

Publisher's version (útgefin grein) ; 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. ; This work was supported by Innovative Medicines Initiative Joint Undertaking Grant Nos. 115008 (NEWMEDS [to KS]) and 115300 (EUAIMS [to KS]), of which resources were composed of European Federation of Pharmaceutical Industries and Associations in-kind contribution and financial contribution from European Union Seventh Framework Programme (EU-FP7/2007-2013) Grant No. 602450 (IMAGEMEND) and FP7-People-2011-IAPP Grant No. 286213 (PsychDPC); Wellcome Trust Strategic Award "DEFINE" Grant No. 100202/Z/12/Z (to JH); and core support from the Neuroscience and Mental Health Research Institute , Cardiff University (PhD grant to AS). Approval for this study was obtained from the National Bioethics Committee of Iceland and the Icelandic Data Protection Authority. ; Peer Reviewed