Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
PLoS One. 2013 Jul 25;8(7):e70302. doi: 10.1371/journal.pone.0070302. Print 2013.
The post-synaptic density (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects). Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02), although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects). The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively. However, this could not be replicated in case-control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes.
谷氨酸能突触的突触后密度 (PSD) 含有许多对维持突触动力学至关重要的蛋白质。在包括精神分裂症在内的神经精神疾病中，这种基质中的蛋白质表达水平的改变是一个显著的现象，其中认知功能受损。为了研究 PSD 基因中表达的基因与精神分裂症的遗传关系，对 PSD 基因（如 DLG4、DLG1、PICK1 和 MDM2）中的遗传变异进行了基于家系的关联分析，使用日本样本（124 个家系，n = 376 个受试者）。结果表明，来自 DLG4 基因的 rs17203281 变体与 C 等位基因的优先传递显著相关（p = 0.02），尽管在进行多次测试校正后，这种相关性消失了。对该变体的复制分析在一个中国精神分裂症队列（293 个家系，n = 1163 个受试者）或一个日本病例对照样本（n = 4182 个受试者）中没有发现关联。精神分裂症患者死后脑组织样本中的 DLG4 表达水平与对照组相比没有明显变化。有趣的是，DLG4 中的一个包含 rs2242449、rs17203281、rs390200、rs222853 和 rs222837 的 5 个标记单倍型以特定人群的方式富集，其中序列 A-C-C-C-A 和 G-C-C-C-A 分别在日本（p = 0.0009）和中国（p = 0.0007）精神分裂症家系样本中积累。然而，在病例对照样本中无法复制这一结果。在这些样本中，其他候选基因中的变体都没有表现出任何显著的相关性。目前的研究强调了 DLG4 在精神分裂症发病机制中的潜在作用，证据是单倍型关联，并需要进一步对这些单倍型内的变体进行密集筛选。
