精神分裂症患者的连接组失连接和皮质基因表达。

Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia.

机构信息

Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.

Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands; Center for Neurobehavioral Genetics and Department of Human Genetics , University of California Los Angeles, Los Angeles, California.

出版信息

Biol Psychiatry. 2017 Mar 15;81(6):495-502. doi: 10.1016/j.biopsych.2016.07.012. Epub 2016 Jul 27.

DOI:10.1016/j.biopsych.2016.07.012

PMID:27720199

Abstract

BACKGROUND

Genome-wide association studies have identified several common risk loci for schizophrenia (SCZ). In parallel, neuroimaging studies have shown consistent findings of widespread white matter disconnectivity in patients with SCZ.

METHODS

We examined the role of genes in brain connectivity in patients with SCZ by combining transcriptional profiles of 43 SCZ risk genes identified by the recent genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium with data on macroscale connectivity reductions in patients with SCZ. Expression profiles of 43 Psychiatric Genomics Consortium SCZ risk genes were extracted from the Allen Human Brain Atlas, and their average profile across the cortex was correlated to the pattern of cortical disconnectivity as derived from diffusion-weighted magnetic resonance imaging data of patients with SCZ (n = 48) and matched healthy controls (n = 43).

RESULTS

The expression profile of SCZ risk genes across cortical regions was significantly correlated with the regional macroscale disconnectivity (r = .588; p = .017). In addition, effects were found to be potentially specific to SCZ, with transcriptional profiles not related to cortical disconnectivity in patients with bipolar I disorder (diffusion-weighted magnetic resonance imaging data; 216 patients, 144 controls). Further examination of correlations across all 20,737 genes present in the Allen Human Brain Atlas showed the set of top 100 strongest correlating genes to display significant enrichment for the disorder, potentially identifying new genes involved in the pathophysiology of SCZ.

CONCLUSIONS

Our results suggest that under disease conditions, cortical areas with pronounced expression of risk genes implicated in SCZ form central areas for white matter disconnectivity.

摘要

背景

全基因组关联研究已经确定了几个与精神分裂症（SCZ）相关的常见风险基因座。与此同时，神经影像学研究显示精神分裂症患者存在广泛的白质连接中断。

方法

我们通过将最近由精神分裂症工作组的精神疾病基因组学联盟进行的全基因组关联研究确定的 43 个 SCZ 风险基因的转录谱与精神分裂症患者的宏观连接减少数据相结合，研究了基因在精神分裂症患者大脑连接中的作用。从 Allen 人类大脑图谱中提取了 43 个精神疾病基因组学联盟 SCZ 风险基因的表达谱，并将其在皮质上的平均图谱与从精神分裂症患者（n = 48）和匹配的健康对照者（n = 43）的弥散加权磁共振成像数据中得出的皮质连接中断模式相关联。

结果

皮质区域 SCZ 风险基因的表达谱与区域宏观连接中断显著相关（r =.588；p =.017）。此外，研究结果表明这些效应可能是 SCZ 特有的，在双相 I 障碍患者的弥散加权磁共振成像数据中（216 名患者，144 名对照者），转录谱与皮质连接中断无关。进一步检查 Allen 人类大脑图谱中存在的所有 20737 个基因的相关性显示，前 100 个相关性最强的基因集显著富集了该疾病，可能鉴定出参与 SCZ 病理生理学的新基因。