A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain
A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain
复制标题
DOI：
10.1038/mp.2008.148
复制
发表时间：
2010-07-01
影响因子：
11
通讯作者：
Jamain, S.
中科院分区：
文献类型：
--
作者：
Etain, B.;Dumaine, A.;Jamain, S.
双相情感障碍（BD）是最常见和最持久的精神疾病之一。早发性BD已被证明是最严重和家族性的形式。我们最近对早发性BD的同胞进行了全基因组连锁分析，结果表明20 p12区域在我们的家族中比预期的更频繁地共享。突触体相关蛋白SNAP 25是触发囊泡融合和神经递质释放所必需的突触前质膜蛋白，并且在双相情感障碍患者的尸检研究中已经报道了其异常蛋白水平。我们推测位于染色体20 p12上的SNAP 25编码基因的变异可能影响早发性BD的易感性。我们对197例早发性BD患者、202例晚发性BD患者和136例未受影响的受试者进行SNAP 25突变筛查和病例对照关联研究。此外，我们分析了60个脑中两种SNAP 25亚型的表达水平。我们发现一个位于启动子区的变异与早发性BD相关，但与晚发性亚组无关。此外，该变体的纯合子个体在前额叶皮层中表现出显著更高的SNAP 25 b表达水平。这些结果表明，SNAP 25的变化，与前额叶皮层的基因表达水平增加，可能易患早发性BD。需要进一步分析该基因，以及分析编码SNAP 25蛋白伴侣的基因，以了解这些分子机制在BD中的影响。Molecular Psychiatry（2010）15，748-755; doi：10.1038/mp.2008.148; 2009年1月6日在线发表
Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Early-onset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD. Molecular Psychiatry (2010) 15, 748-755; doi:10.1038/mp.2008.148; published online 6 January 2009