Bray Nicholas J, Preece Anna, Williams Nigel M, Moskvina Valentina, Buckland Paul R, Owen Michael J, O'Donovan Michael C
Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, UK.
Hum Mol Genet. 2005 Jul 15;14(14):1947-54. doi: 10.1093/hmg/ddi199. Epub 2005 May 25.
The DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far to identify any specific susceptibility variants and by the absence of any demonstrated function associated with any of the risk haplotypes. In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex. Subsidiary analyses suggest that risk haplotypes identified in other sample groups of white European ancestry also index lower DTNBP1 expression, whereas putative 'protective' haplotypes index high DTNBP1 expression. Our data indicate that variation in the DTNBP1 gene confers susceptibility to schizophrenia through reduced expression, and that this, therefore, represents a primary aetiological mechanism in the disorder.
编码dysbindin的DTNBP1基因目前通常被认为是精神分裂症的一个易感基因。然而，由于各研究之间在相关单倍型的确切性质方面缺乏可重复性，由于迄今为止未能鉴定出任何特定的易感变异体，以及由于缺乏与任何风险单倍型相关的任何已证实的功能，因此对这一假设的确信程度不得不有所缓和。在本研究中，我们表明一个明确的精神分裂症风险单倍型标记了一个或多个顺式作用变异体，这些变异体导致人类大脑皮层中DTNBP1 mRNA表达相对降低。辅助分析表明，在其他欧洲白人血统样本组中鉴定出的风险单倍型也表明DTNBP1表达较低，而假定的“保护性”单倍型则表明DTNBP1表达较高。我们的数据表明，DTNBP1基因的变异通过降低表达赋予了精神分裂症易感性，因此，这代表了该疾病的一种主要病因机制。
