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Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white-matter structures

Drakesmith, Mark, Parker, Greg D., Smith, Jacqueline, Linden, Stefanie C., Rees, Elliott, Williams, Nigel, Owen, Michael J., van den Bree, Marianne, Hall, Jeremy, Jones, Derek K. and Linden, David E. J. 2019. Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white-matter structures. Translational Psychiatry 9 (1) , 102. 10.1038/s41398-019-0440-7

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Abstract

Genomic copy number variants (CNVs) are amongst the most highly penetrant genetic risk factors for neuropsychiatric disorders. The scarcity of carriers of individual CNVs and their phenotypical heterogeneity limits investigations of the associated neural mechanisms and endophenotypes. We applied a novel design based on CNV penetrance for schizophrenia (Sz) and developmental delay (DD) that allows us to identify structural sequelae that are most relevant to neuropsychiatric disorders. Our focus on brain structural abnormalities was based on the hypothesis that convergent mechanisms contributing to neurodevelopmental disorders would likely manifest in the macro- and microstructure of white matter and cortical and subcortical grey matter. Twenty one adult participants carrying neuropsychiatric risk CNVs (including those located at 22q11.2, 15q11.2, 1q21.1, 16p11.2 and 17q12) and 15 age- and gender-matched controls underwent T1-weighted structural, diffusion and relaxometry MRI. The macro- and microstructural properties of the cingulum bundles were associated with penetrance for both developmental delay and schizophrenia, in particular curvature along the anterior-posterior axis (Sz: pcorr = 0.026; DD: pcorr = 0.035) and intracellular volume fraction (Sz: pcorr = 0.019; DD: pcorr = 0.064). Further principal component analysis showed alterations in the interrelationships between the volumes of several midline white-matter structures (Sz: pcorr = 0.055; DD: pcorr = 0.027). In particular, the ratio of volumes in the splenium and body of the corpus callosum was significantly associated with both penetrance scores (Sz: p = 0.037; DD; p = 0.006). Our results are consistent with the notion that a significant alteration in developmental trajectories of midline white-matter structures constitutes a common neurodevelopmental aberration contributing to risk for schizophrenia and intellectual disability.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Springer Nature
ISSN: 2158-3188
Date of First Compliant Deposit: 1 March 2019
Date of Acceptance: 13 February 2019
Last Modified: 17 Apr 2019 12:17
URI: http://orca.cf.ac.uk/id/eprint/120108

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