From linkage to genes conferring susceptibility to schizophrenia: investigation of candidate genes on chromosome 6p

精神分裂症是一种潜在的致残障碍，对个人、家庭和社区都有严重影响。今天出生的孩子患精神分裂症的风险约为1%。遗传因素在精神分裂症的发病中起主要作用，但环境因素也起到了作用。精神分裂症的分子原因尚未被发现，因为关于复杂的大脑功能及其疾病的知识正在迅速增加。对涉及大脑功能和功能障碍的遗传因素的识别和表征可能会为精神分裂症的神经和分子机制带来新的见解。有证据表明，包括我们在内的几个小组报告的证据表明，在家族中与精神分裂症共分离的基因位于6p染色体上的一个区域。通过对这一区域的精细基因解剖，我们和其他人发现编码异常结合蛋白的基因与精神分裂症有关。我们的目的是找出dybindin基因的DNA变异体(S)，以及可能位于染色体6p上的其他候选基因的变异体。我们将使用最先进的方法和关于基因和DNA变异的信息，这是通过人类基因组计划提供的。一旦确定了基因变异，我们将分析精神分裂症患者死后脑组织中的基因表达，并研究已确定基因编码的蛋白质的分布和功能。我们的最终目标是确定特定的遗传因素，这些因素与精神分裂症的大脑功能障碍有关。如果成功，这应该会带来关于这种疾病原因的线索。此外，这项研究将有助于开发早期诊断和预防的方法。可能，最重要的结果将是确定新的和更具体的药理治疗的分子靶点，这些治疗最终可能取代目前以症状为导向的抗精神病药物。

Schizophrenia is a potentially disabling disorder with severe impact on the individual, the family and the community. The risk that a child born today will develop schizophrenia is about 1%. Genetic factors play a major predisposing role in schizophrenia, but environmental factors contribute as well. The molecular causes of schizophrenia are yet to be discovered, as knowledge about complex brain functions and their disorders is rapidly increasing. The identification and characterisation of genetic factors involved in brain function and dysfunction is likely to bring about novel insights into the neural and molecular mechanisms underlying schizophrenia. There is evidence, reported by several groups including our own, that genes, co-segregating with schizophrenia in families are located in a region on chromosome 6p. By fine-grain genetic dissection of this region, we and others have found that the gene coding for the protein dysbindin is associated with schizophrenia. Our aim is to identify the DNA variant(s) in the dysbindin gene, as well as variants in other candidate genes that may be located in chromosome 6p. We will use state-of-the art methods and information on genes and DNA variants, made available through the Human Genome Project. Once genetic variants are identified, we will analyse gene expression in post mortem brain tissue of persons with schizophrenia and study the distribution and function of the proteins coded by the identified genes. Our ultimate goal is to identify specific genetic factors involved in the brain dysfunction characterising schizophrenia. If successful, this should lead to clues about the causes of the disorder. In addition, the study will contribute to the development of methods for early diagnosis and prevention. Possibly, the most important outcome will be the identification of molecular targets for novel and more specific pharmacological treatments that may eventually replace current symptom-oriented antipsychotic medications.