Developmental Neurogenomics Unit, Human Genetics Branch, National Institute of Mental Health, Bethesda, Maryland 20892.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5T 1R8, Canada.
eNeuro. 2018 Nov 29;5(5). doi: 10.1523/ENEURO.0265-18.2018. eCollection 2018 Sep-Oct.
Sex chromosome aneuploidy (SCA) increases risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. Thus, SCA offers a genetics-first model for understanding the biological basis of psychopathology. Additionally, the sex-biased prevalence of many psychiatric disorders could potentially reflect sex chromosome dosage effects on brain development. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes ( = 132) and typically developing controls ( = 166). After adjustment for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume adjustment, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population ( = 79). Hippocampal volume was insensitive to SCA after adjustment for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area crossing the hippocampal tail. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.
性染色体非整倍体（SCA）增加了几种与边缘系统相关的精神疾病的风险，包括情绪和自闭症谱系障碍。因此，SCA 为理解精神病理学的生物学基础提供了一个遗传优先的模型。此外，许多精神疾病的性别偏向性流行可能反映了性染色体剂量效应对大脑发育的影响。为了阐明边缘解剖结构如何在性别和性染色体组成上发生变化，我们在一个独特的携带多余性染色体的大样本患者（= 132）和正常发育对照（= 166）中描述了杏仁核和海马体的结构。在调整大脑大小的性别差异后，核型正常的男性（XY）和女性（XX）在结构的体积或形状上没有差异。相比之下，所有 SCA 都与相对于性腺匹配的对照组相比，杏仁核体积降低有关。该效应在三种不同的总脑体积调整方法中均很稳健，包括在单独的正常发育人群（= 79）中为这些结构推导规范缩放规则的同态分析。在调整总脑体积后，海马体体积不受 SCA 的影响。然而，基于表面的分析表明，无论特定核型如何，SCA 都与杏仁核和海马体中形状变化的空间特异性模式一致相关。特别是，SCA 伴随着围绕杏仁核基底内侧核和穿过海马尾部的区域的收缩。这些结果表明 SCA 作为一种模型的强大功能，可以理解拷贝数变异如何引发与精神疾病相关的大脑系统变化。
