文献出处：Biol Psychiatry. 2011 02 15;69(4):353-9. Epub 2010 Dec 24.
期刊影响因子：8.926
了解
双相情感障碍的遗传学特点可促使我们找到新的疗法，但鉴别与该病相关的特定遗传变异存在一定困难。
《生物精神病学》杂志上的一项新研究提到了一种名为Piccolo的脑蛋白，这种蛋白与双相情感障碍的遗传风险有关。在神经蛋白族群中，Piccolo是一种蛋白质家族(包括另一种名为Bassoon的蛋白)的成员之一。Piccolo位于神经细胞的末端，有利于神经细胞释放化学信使。
Choi及其同事进行了一项创造性的研究，揭示了Piccolo (PCLO) 的基因编码(与双相情感障碍的遗传风险有关)。
他们从生前诊断为双相情感障碍的患者与死前无精神疾病的人身上提取皮层组织，对比了二者的基因表达模式。经分析确定了45个显著改变mRNA水平的基因与基因变异，并借助这一信息缩小了在遗传学研究中要探索的基因组范围。
随后，他们检测了尸检组织中改变表达水平的基因附近的遗传标记（称为单核苷酸多态性或SNPs的小型DNA序列变异）。其中一种PCLO遗传标记(SNP rs13438494)在分析中表现得尤为明显，由此表明PCLO的变异可导致双相情感障碍的发生。
“我们采用了一种创新性的方法，将基因表达与特征明显的尸体脑部处获得的基因变异资料关联起来，然后结合一项针对全基因组关联研究的大型荟萃分析” Kwang Choi博士称“如果上述研究能被复制，最终在复杂的遗传性疾病中可建立一种基因表达与全基因组关联研究的联系。”
“这项研究很好地说明了熟练掌握脑生物学方面的知识有助于指导我们的遗传学研究”，《生物精神病学》杂志主编John Krystal博士补充道。
医脉通推荐英文摘要Biol Psychiatry. 2011 Feb 15;69(4):353-9.
Gene expression and genetic variation data implicate PCLO in bipolar disorder.
Choi KH, Higgs BW, Wendland JR, Song J, McMahon FJ, Webster MJ.
(Stanley Laboratory of Brain Research, Rockville, Maryland, USA. )
BACKGROUND: Genetic variation may contribute to differential gene expression in the brain of individuals with psychiatric disorders. To test this hypothesis, we identified genes that were differentially expressed in individuals with bipolar disorder, along with nearby single nucleotide polymorphisms (SNPs) that were associated with expression of the same genes. We then tested these SNPs for association with bipolar disorder in large case-control samples.
METHODS: We used the Stanley Genomics Database to extract gene expression and SNP microarray data from individuals with bipolar disorder (n = 40) and unaffected controls (n = 43). We identified 367 genes that were differentially expressed in the prefrontal cortex of cases vs. controls (fold change > 1.3 and FDR q-value < .05) and 45 nearby SNPs that were associated with expression of those same genes (FDR q-value < .05). We tested these SNPs for association with bipolar disorder in a meta-analysis of genome-wide association studies (GWAS) including 4,936 cases and 6,654 healthy controls.
RESULTS: We identified 45 SNPs that were associated with expression of differentially expressed genes, including HBS1L (15 SNPs), HLA-DPB1 (15 SNPs), AMFR (8 SNPs), PCLO (2 SNPs) and WDR41 (2 SNPs). Of these, one SNP (rs13438494), in an intron of the piccolo (PCLO) gene, was significantly associated with bipolar disorder (FDR adjusted p < .05) in the meta-analysis of GWAS.
CONCLUSIONS: These results support the previous findings implicating PCLO in mood disorders and demonstrate the utility of combining gene expression and genetic variation data to improve our understanding of the genetic contribution to bipolar disorder.
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