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

Mark Drakesmith,Michael J Owen,Nigel Williams,Marianne Van Den Bree,Greg D Parker,Jacqueline Smith,Stefanie C Linden,David E J Linden,Jeremy Hall,Derek K Jones,Elliott Rees

doi:10.1038/s41398-019-0440-7

Mark Drakesmith, Michael J Owen + Show 9 more

Open Access

https://doi.org/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.

Highlights

Genetic variants are associated with neurodevelopmental disorders across conventional diagnostic classifications
White-matter morphology Shape analysis revealed significant alteration of one component of the left cingulum bundle that was significantly correlated with both PSz (t = 4.195, p = 2.11 × 10–4, pcorr = 0.026) and PDD (t = 4.06, p = 3.1 × 10−5, pcorr = 0.035)
In this study we investigated morphological and microstructural alterations associated with copy number variants (CNVs) with high penetrance for schizophrenia and developmental delay

Summary

Introduction

Genetic variants are associated with neurodevelopmental disorders across conventional diagnostic classifications. The mechanisms through which these genetic variants affect brain and behaviour are poorly understood, but genetic imaging studies in people selected for polygenic risk[3] or CNV carriers[4] can elucidate changes in brain development, structure and function that are not confounded by secondary disease effects. Because of their high penetrance, CNVs are suited to translational studies elucidating disease mechanisms. For most of the pathogenic CNVs identified for schizophrenia and Drakesmith et al Translational Psychiatry (2019)9:102

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