Familial Schizophrenia Spectrum Personality Disorders

描述(申请人提供)：识别与疾病相关的遗传效应是精神分裂症研究的一个主要焦点。这些努力是多方面的，最终目标是描述从特定基因变异到神经元功能变化再到行为和功能障碍的因果路径。精神分裂症的诊断可能反映了几种这样的因果路径的不同组合，因此具有不同的表型集合，每一种表型都与反映一小部分基因影响的特定神经认知缺陷有关。因此，基于临床表型的遗传发现可能会有所不同，这可能解释了重复复制已识别的疾病位点的反复失败的原因。根据临床诊断定义受影响的人也忽略了这样一种可能性，即一些亲属虽然在临床上没有受到影响，但也存在疾病风险的方面。环境因素也有牵连，增加了该病的病因复杂性。鉴于这些复杂性，迫切需要能够反映疾病风险具体方面的表型。标记疾病风险的特定方面的内表型的识别、验证和应用对未来的遗传学研究、检测基因与环境的相互作用、病理生理学研究和预防研究具有重要的意义。我们建议进行一项家庭病例对照研究，以确认假定的神经生理和认知表型与精神分裂症易感性之间的关联(S)，并确定这些缺陷是否与病例亲属中存在精神分裂症、谱系人格(SSP)症状有关，排除SSP症状本身的影响。我们建议检查神经生理/认知测量之间的关系，以确定哪些缺陷反映了共同的潜在表型，哪些代表了疾病风险的独立方面。我们将根据病例先证者是否存在缺陷来确定病例亲属中单一缺陷和复合缺陷的不同风险。在家庭内部，将审查牵连措施的相关性，以得出遗传力的估计，并审查遗传和共同环境影响的相对贡献。我们还建议检查神经生理表型和精神分裂症相关症状域之间的关系。我们计划招募120名患者和所有可用的一级亲属(300名，60名患有SSP)。对于每个病例先证者，我们将使用定向电话呼叫(TTC)程序确定年龄(3岁)、性别、种族、县匹配对照先证者。我们将招募所有可用的和符合条件的对照亲属(300人)。我们也会从社区中招募一组没有精神病家族史而表现为SSP的人，以检查SSP症状本身的影响。将收集临床信息、电生理和认知测量，并使用标准的家庭病例对照分析程序在各组之间进行比较。

DESCRIPTION (provided by applicant): Identifying disease-related genetic effects is a major focus in schizophrenia research. Efforts have been multifaceted with the ultimate goal to describe a causal path from specific genetic variants to changes in neuronal functioning to behavioral and functional impairments. The schizophrenia diagnosis likely reflects a heterogeneous combination of several such causal paths,and is therefore characterized by a varying collection of phenotypes each associated with specific neurocognitive deficits reflecting the effects of a small subset of genes. Thus genetic findings based on the clinical phenotype are likely to vary, which may explain repeated failures to replicate identified disease loci. Defining who is affected based on the clinical diagnosis also ignores the likelihood that some relatives, although clinically unaffected, also carry aspects of disease risk. Environmental factors are also implicated, adding to the etiologic complexity of the disease. In light of these complexities there is a critical need for phenotypes that reflect specific aspects of disease risk. The identification, validation, and application of endophenotypes that mark specific aspects of disease risk has important implications for future genetic studies, studies examining the interaction of genes and environment, studies ofpathophysiology, and prevention research. We propose to conduct a family case-control study to confirm the association(s) between putative neurophysiological and cognitive phenotypes and schizophrenia liability and to determine if these deficits are associated with the presence of schizophrenia,spectrum personality (SSP) symptoms among case relatives ruling out the effects of SSP symptoms per se. We propose to examine the relationships among neurophysiological/cognitive measures to determine which deficits reflect a common underlying phenotype and which represent independent aspects of disease risk. We will determine the differential risk of single and composite deficits among case relatives based on the presence/absence of deficits in case probands. Within family correlations for implicated measures will be examined to derive estimates of heritability and to examine the relative contributions of genetic and shared environmental effects. We also propose to examine the relationships between neurophysiological phenotypes and schizophrenia-related symptom domains. We plan to recruit 120 patients and all available first-degree relatives (300, 60 with SSP). For each case proband, we will identify an age (+ 3 yrs), sex, race, county matched control proband using targeted telephone calling (TTC) procedures. We will recruit all available and eligible control relatives (300). We will also recruit a separate group of persons from the community who exhibit SSP in the absence of a family history of psychotic disorders in order to examine the effects of SSP symptoms per se. Clinical information, electrophysiological and cognitive measures will be collected and compared among the groups using standard family case control analytic procedures.