PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA

描述(由申请人提供)：多年来，该实验室一直专注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--认为有精神分裂症特征的障碍、眼球跟踪功能障碍和累及额颌交界处的颅面异常--在澄清精神分裂症易感基因的神经生物学解释方面特别突出。这些特征中的每一种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的家族数据与单基因传播模型一致，因此可能澄清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巨大投资已经产生了大量有希望的候选基因和染色体区域。我们在确定SRT的特征方面取得的进展使我们处于一个理想的位置，可以确定这些SRT中是否有任何与精神分裂症的已识别基因和热斑“区域有关。当然，我们认识到，不是所有报告的联系都是可复制的，但其中一些是真实的可能性很高，对候选基因座采取包容性观点所增加的成本是适度的。我们的能力分析表明，在精神分裂症先证者的家庭中，受SRT影响的个体密度足够高，以至于给定与SRT相关的候选基因，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有关的基因座被证明与任何SRT有关，这将为在疾病表型及其遗传基础之间建立神经生物学桥梁开辟道路，并将大大增加人们对已报道的联系的信心。由于我们的实验室长期参与研究精神分裂症相关的特征，大量的家庭已经获得并就这些特征进行了彻底的研究，以及我们的统计和分子遗传学合作者的专业知识，我们的实验室处于开展这些研究的独特地位。

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.