Kato T, Iwayama Y, Kakiuchi C, Iwamoto K, Yamada K, Minabe Y, Nakamura K, Mori N, Fujii K, Nanko S, Yoshikawa T
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Mol Psychiatry. 2005 Nov;10(11):1045-55. doi: 10.1038/sj.mp.4001719.
We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.
我们之前报道过，在双相情感障碍、精神分裂症和重度抑郁症患者的大脑中，LIM（ENH、PDLIM5）的表达水平显著且普遍升高。双相情感障碍和精神分裂症患者来源的淋巴母细胞中LIM的表达降低。据报道，LIM蛋白在将蛋白激酶C与钙通道联系起来方面发挥着重要作用。这些发现提示了LIM在双相情感障碍和精神分裂症病理生理学中的作用。为了进一步研究LIM在这些精神障碍中的作用，我们进行了基因表达分析的重复研究，并开展了基因关联研究。在从斯坦利阵列数据库获得的独立样本集中证实了LIM的上调。未观察到样本pH值或药物治疗的影响。基因关联研究揭示了单核苷酸多态性（SNP）1（rs10008257）与双相情感障碍的关联。在一个独立样本集中，靠近SNP1的SNP2（rs2433320）与双相情感障碍相关。在所有样本中，这两个SNP的单倍型与双相情感障碍相关。在精神分裂症的病例对照分析和基于家系的关联分析中未观察到关联。这些结果表明，LIM上游区域的SNP可能赋予双相情感障碍遗传风险。
