Callicott Joseph H, Straub Richard E, Pezawas Lukas, Egan Michael F, Mattay Venkata S, Hariri Ahmad R, Verchinski Beth A, Meyer-Lindenberg Andreas, Balkissoon Rishi, Kolachana Bhaskar, Goldberg Terry E, Weinberger Daniel R
Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, Division of Intramural Research, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8627-32. doi: 10.1073/pnas.0500515102. Epub 2005 Jun 6.
Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.
精神分裂症缺失1基因（DISC1）是一个很有潜力的精神分裂症候选基因，主要在海马体中表达。我们对覆盖DISC1基因的12个单核苷酸多态性（SNP）进行了分型。一个跨越该基因83 kb的三SNP单倍型[hCV219779（C）-rs821597（G）-rs821616（A）]在一个基于家系的样本中与精神分裂症相关（P = 0.002）。该单倍型内一个常见的非保守SNP（Ser704Cys）（rs821616）与精神分裂症相关（P = 0.004）。基于DISC1在海马体中的主要表达，我们推测Ser704Cys处的等位基因变异会对海马体结构和功能产生可测量的影响，这可通过特定的与海马体相关的中间表型来测定。除了在精神分裂症中的过度传递外，Ser等位基因还与健康受试者海马体结构和功能的改变有关，包括海马体灰质体积减少以及在功能磁共振成像测定的几项认知任务中，海马体的参与情况发生改变。这些一致的数据表明，DISC1内的等位基因变异，无论是在Ser704Cys处还是由其监测的单倍型，都会增加患精神分裂症的风险，并且这种效应的机制涉及海马体结构和功能的改变。
