PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA

与精神分裂症相关的基因的多效性

• 批准号: 7315378
• 负责人: DEBORAH L LEVY
• 金额: $ 55.4万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315378
• 关键词: Accounting; Affect; Biological; Candidate Disease Gene; Clinical; Cognitive; Collection; Compatible; Complex; Data; Disease; Dominant Genes; Dysmorphology; Eye; Family; First Degree Relative; Functional disorder; Gene Family; General Population; Genes; Genetic; Genetic Markers; Goals; Individual; Investments; Laboratories; Light; Link; Lod Score; Measures; Methods; Modeling; Molecular Genetics; National Institute of Mental Health; Neurobiology; Nuclear; Numbers; Pathology; Pathway interactions; Phenocopy; Phenotype; Physiological; Positioning Attribute; Predisposition; Probability; Process; Range; Recurrence; Relative (related person); Reporting; Risk; Risk Factors; Sampling; Schizophrenia; Semantics; Siblings; Smooth Pursuit; Spottings; Symptoms; System; Thinking; Work; cost; craniofacial; density; design; disease phenotype; endophenotype; genetic linkage; interest; oculomotor; proband; success; trait; transmission process

DESCRIPTION (provided by applicant): For many years this laboratory has focused intensively on characterizing schizophrenia-related traits (SRTs) as qualitative and quantitative phenotypes for schizophrenia. Three of these SRTs - thought disorder with schizophrenic features, eye tracking dysfunction and a craniofacial anomaly involving the frontonasal-maxilllary junction - stand out as especially probative for clarifying the neurobiological interpretation of schizophrenia susceptibility loci. Each of these traits has a much higher recurrence in relatives of schizophrenics than in schizophrenics. Moreover, unlike schizophrenia, which is generally thought to involve a number of co-acting genes, the family data on the SRTs are consistent with monogenic transmission models, and may therefore clarify the complex genetics of schizophrenia. The massive investment by NIMH in searching for genes for schizophrenia has resulted in an impressive number of promising candidate genes and chromosomal regions. Our progress in characterizing SRTs places us in an ideal position to determine whether any of these SRTs is linked to identified genes and "warm spot" regions for schizophrenia. We recognize, of course, that not all of the reported linkages will be replicable, but the probability is high that some of them are authentic, and the added cost of taking an inclusive view of the candidate loci is modest. Our power analyses show that the density of individuals affected with the SRTs in families of a schizophrenic proband is sufficiently high that, given a candidate locus associated with the SRT, the probability of our being able to detect that relationship is very high. If any of the genetic loci that have been linked to schizophrenia can be shown to be linked to any of the SRTs, it would open the way for building a neurobiological bridge between the disease phenotype and its genetic underpinnings, and it would add considerably to the confidence one can have in the reported linkages. Because of our laboratory's long involvement in investigating schizophrenia-related traits, the substantial number of families already acquired and thoroughly studied with respect to these traits and the expertise of our statistical and molecular genetics collaborators, our laboratory is uniquely positioned to carry out these studies.

描述（由申请人提供）：多年来，该实验室一直致力于将精神分裂症相关特征（SRT）表征为精神分裂症的定性和定量表型。其中三个 SRT——具有精神分裂症特征的思维障碍、眼球追踪功能障碍和涉及额鼻-上颌骨交界处的颅面异常——对于澄清精神分裂症易感位点的神经生物学解释尤其具有证明作用。这些特征在精神分裂症患者亲属中的复发率比在精神分裂症患者中高得多。此外，与通常认为精神分裂症涉及许多共同作用的基因不同，SRT 的家族数据与单基因传播模型一致，因此可能阐明精神分裂症的复杂遗传学。 NIMH 在寻找精神分裂症基因方面投入了大量资金，已经产生了大量有希望的候选基因和染色体区域。我们在表征 SRT 方面取得的进展使我们处于理想的位置，可以确定这些 SRT 中的任何一个是否与已识别的基因和精神分裂症的“热点”区域有关。当然，我们认识到，并非所有报告的联系都是可复制的，但其中一些联系的真实性的可能性很高，并且对候选基因座采取包容性观点的额外成本是适度的。我们的功效分析表明，精神分裂症先证者家族中受 SRT 影响的个体密度足够高，因此，考虑到与 SRT 相关的候选位点，我们能够检测到这种关系的概率非常高。如果任何与精神分裂症相关的基因位点可以被证明与任何 SRT 相关，那么它将为在疾病表型与其遗传基础之间建立神经生物学桥梁开辟道路，并且将大大增加人们对所报告的联系的信心。由于我们实验室长期参与精神分裂症相关特征的研究，大量家庭已经获得并深入研究了这些特征，以及我们的统计和分子遗传学合作者的专业知识，我们的实验室在开展这些研究方面具有独特的优势。