基因关联与脑形态学研究以及8号染色体短臂22区中心粒旁物质1（PCM1）基因在精神分裂症易感性中的作用
Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia.
作者信息
Gurling Hugh M D, Critchley Hugo, Datta Susmita R, McQuillin Andrew, Blaveri Ekaterina, Thirumalai Srinivasa, Pimm Jonathan, Krasucki Robert, Kalsi Gursharan, Quested Digby, Lawrence Jacob, Bass Nicholas, Choudhury Khalid, Puri Vinay, O'Daly Owen, Curtis David, Blackwood Douglas, Muir Walter, Malhotra Anil K, Buchanan Robert W, Good Catriona D, Frackowiak Richard S J, Dolan Raymond J
机构信息
Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, United Kingdom.
出版信息
Arch Gen Psychiatry. 2006 Aug;63(8):844-54. doi: 10.1001/archpsyc.63.8.844.
CONTEXT
There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies.
OBJECTIVES
To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging.
DESIGN
Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia.
MAIN OUTCOME MEASURES
Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping.
RESULTS
The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex.
CONCLUSIONS
The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.
背景
多项家族连锁研究发现了与8号染色体p21 - 22区域精神分裂症易感性位点的连锁证据。
目的
在8号染色体p22区域精细定位并鉴定精神分裂症的一个易感基因，并使用磁共振成像研究这种遗传易感性对异常脑结构内表型的影响。
设计
通过在多个患病家族、病例对照样本和三联体样本中寻找遗传标记与精神分裂症之间的连锁不平衡，对8号染色体p22区域的易感基因进行精细定位和鉴定。使用基于体素的形态测量法和磁共振成像的统计参数映射来检查与中心粒周物质1（PCM1）等位基因相关的脑形态变化。研究地点和患者 一个由13个精神分裂症多发的大家庭组成的家族样本，来自英国和苏格兰的2个精神分裂症病例对照样本，以及一个来自美国的包含父母和1名患精神分裂症子女的精神分裂症三联体样本。
主要观察指标
使用家族样本检测PCM1基因座多态性与精神分裂症之间的传递不平衡，以及在病例对照和三联体样本中检测等位基因关联。使用统计参数映射的基于体素的形态测量法。
结果
家族样本和三联体样本均显示PCM1基因座中的标记D85261与精神分裂症之间存在显著的传递不平衡。来自英国的病例对照样本也发现PCM1基因标记与精神分裂症之间存在显著的等位基因关联。与非PCM1相关精神分裂症患者相比，继承了PCM1遗传易感性的病例基于体素的形态测量显示眶额皮质灰质体积显著相对减少，相比之下，非PCM1相关精神分裂症患者颞极、海马和颞下回皮质灰质体积减少。
结论
PCM1基因与精神分裂症易感性有关，并与眶额灰质体积缺陷相关。
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