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Analysis of diffusion tensor imaging data from the UK Biobank confirms dosage effect of 15q11.2 copy number variation on white matter and shows association with cognition

Silva, Ana I., Kirov, George, Kendall, Kimberley M., Bracher-Smith, Mathew, Wilkinson, Lawrence S., Hall, Jeremy, Ulfarsson, Magnus O., Walters, G. Bragi, Stefansson, Hreinn, Stefansson, Kari, Linden, David E.J. and Caseras, Xavier 2021. Analysis of diffusion tensor imaging data from the UK Biobank confirms dosage effect of 15q11.2 copy number variation on white matter and shows association with cognition. Biological Psychiatry 90 (5) , pp. 307-316. 10.1016/j.biopsych.2021.02.969

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Background Copy number variations at the 15q11.2 BP1-BP2 locus are present in 0.5%–1.0% of the population, and the deletion is associated with several neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to expand these findings using a larger sample of participants (N = 29,166) and higher resolution imaging and by examining the implications for cognitive performance. Methods Diffusion tensor imaging measures from participants with no neurological or psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n = 102) and duplication (n = 113) carriers to a large cohort of control individuals with no neuropsychiatric copy number variants (n = 28,951). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance. Results Deletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum and decreases in the posterior thalamic radiation compared with both duplication carriers and control subjects (who had intermediate values). Compared with control subjects, deletion carriers had lower scores across cognitive tasks, which were partly influenced by white matter. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers. Conclusions These results, together with our previous findings, provide convergent evidence for an effect of 15q11.2 BP1-BP2 on white matter microstructure, this being more pronounced in deletion carriers. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Psychology
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0006-3223
Funders: Wellcome Trust
Date of First Compliant Deposit: 11 May 2021
Date of Acceptance: 23 February 2021
Last Modified: 30 Jan 2022 11:55

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