Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white-matter structures
Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white-matter structures
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DOI：
10.1038/s41398-019-0440-7
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发表时间：
2019-02-25
影响因子：
6.8
通讯作者：
Linden, David E. J.
中科院分区：
文献类型：
--
作者：
Drakesmith, Mark;Parker, Greg D.;Linden, David E. J.
基因组拷贝数变异(CNV)是神经精神疾病最具渗透性的遗传风险因素之一。单个CNV携带者的稀缺性及其表型的异质性限制了相关神经机制和内表型的研究。我们应用了一种基于CNV外显率的新设计，用于治疗精神分裂症(Sz)和发育迟缓(DD)，使我们能够识别与神经精神障碍最相关的结构性后遗症。我们对大脑结构异常的关注是基于这样一个假设，即导致神经发育障碍的趋同机制可能会在白质以及皮质和皮质下灰质的宏观和微观结构中表现出来。21名携带神经精神疾病风险CNV的成人参与者(包括位于22q11.2、15q11.2、1q21.1、16p11.2和17q12的CNV)和15名年龄和性别匹配的对照组接受了T1加权结构、扩散和松弛测量MRI。扣带束的宏观和微观结构特征与发育迟缓和精神分裂症的外显率有关，特别是沿前后轴的曲率(Sz：P(Corr)=0.026；DD：P(Corr)=0.035)和细胞内体积分数(Sz：P(Corr)=0.019；DD：P(Corr)=0.064)。进一步的主成分分析显示，几个中线白质结构的体积之间的相互关系发生了变化(Sz：P(Corr)=0.055；DD：P(Corr)=0.027)。尤其是，两种外显率之间均存在显著的相关性(Sz：P=0.037；Dd；P=0.006)。我们的结果与中线白质结构发育轨迹的显著变化构成了一种常见的神经发育异常的概念是一致的，这一点导致了精神分裂症和智力残疾的风险。
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: p(corr) = 0.026; DD: p(corr) = 0.035) and intracellular volume fraction (Sz: p(corr) = 0.019; DD: p(corr) = 0.064). Further principal component analysis showed alterations in the interrelationships between the volumes of several midline white-matter structures (Sz: p(corr) = 0.055; DD: p(corr) = 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.