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Cited by 36Genomic variations and chromosomal abnormalitiesAdvanced Neuroimaging Techniques and ApplicationsGenetics and Neurodevelopmental Disorders

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

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Silva, Ana I., Ulfarsson, Magnus O., Stefansson, Hreinn, Gustafsson, Omar, Walters, G. Bragi, Linden, David E.J., Wilkinson, Lawrence S., Drakesmith, Mark +3 more·2019·Biological Psychiatry
DOI 10.1016/j.biopsych.2018.11.004PMC PMC6424871
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Abstract

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.

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Authors
Silva, A. I., Ulfarsson, M. O., Stefansson, H., Gustafsson, O., Walters, G. B., Linden, D. E. J., Wilkinson, L. S., Drakesmith, M., Owen, M. J., Hall, J., & Stefansson, K.
Affiliations
  • Cardiff University (GB)
  • deCODE Genetics (Iceland) (IS)
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2019-04
Volume
85
Issue
7
Pages
563-572
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2018.11.004
PMC
PMC6424871
OpenAlex
W2901129802
Cited by
36
References
78
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 10 · 2020: 9 · 2019: 5
FWCI
3.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Opin vísindi (Opin vísindi) (submittedVersion, cc-by)
Funders
  • Innovative Medicines Initiative (115008, 115300)
  • European Union Seventh Framework Programme (602450, 286213)
  • Wellcome Trust Strategic Award (100202/Z/12/Z)
  • Neuroscience and Mental Health Research Institute
  • Cardiff University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
copy number variation, white matter microstructure, fractional anisotropy, CYFIP1, FMRP, fragile X syndrome, internal capsule, brain structure, autism spectrum disorder, schizophrenia
MeSH terms
Adult, Aged, Chromosome Aberrations, Chromosome Deletion, Chromosomes, Human, Pair 15, Female, Humans, Male, Intellectual Disability, Middle Aged, Adaptor Proteins, Signal Transducing, Young Adult, Diffusion Tensor Imaging, DNA Copy Number Variations, Chromosome Duplication, White Matter

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