PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA

描述（由申请人提供）：多年来，本实验室一直专注于定性和定量表征精神分裂症相关性状（srt）。其中三种srt——具有精神分裂症特征的思维障碍、眼动追踪功能障碍和涉及额颌交界处的颅面异常——在阐明精神分裂症易感位点的神经生物学解释方面尤为突出。这些特征在精神分裂症患者亲属中的复发率都比精神分裂症本身高得多。此外，与通常被认为涉及多个共同作用基因的精神分裂症不同，srt的家庭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的大量投资已经产生了数量可观的有希望的候选基因和染色体区域。我们在表征srt方面的进展使我们处于一个理想的位置，以确定这些srt是否与已识别的基因和精神分裂症的“温暖点”区域有关。当然，我们认识到，并非所有报道的联系都是可复制的，但其中一些是真实的可能性很高，并且对候选基因座进行包容性观察的额外成本是适度的。我们的功率分析表明，精神分裂症先证者家庭中受SRT影响的个体密度足够高，因此，给定与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，并且它将大大增加人们对报告的联系的信心。由于我们的实验室长期参与研究精神分裂症相关特征，大量的家庭已经获得并彻底研究了这些特征，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处于独特的地位。

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 craniofaclal anomaly involving the frontonasaimaxillary 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 schizophrenia itself. 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.