Abnormal Eye Movement in Schizophrenia: Genome-Wide Scan

描述：(申请人提供)： 这是这份R01提案的第三份意见书。这项建议的目的是进行全基因组扫描，寻找与精神分裂症相关的内表型的联系，即在平稳追踪眼动(SPEM)任务中导致眼跳频率增加。SPEM异常与精神分裂症有关已有近100年的历史，20多年来一直被认为是精神分裂症的潜在遗传风险标志。在过去的几年里，我们一直专注于确定SPEM中对精神分裂症最特异、对推测的遗传风险最敏感的成分(S)。在SPEM任务中，引导性扫视的频率升高似乎是SPEM功能的一个敏感和特定的组成部分。与普通人群或注意力缺陷/多动障碍、自闭症或双相情感障碍患者相比，精神分裂症患者的主导眼跳频率升高更为常见；精神分裂症患者的亲属更常见；似乎与精神分裂症的假定遗传风险有关；6-80岁可用。此外，领先眼跳频率升高在普通人群中呈三态分布，在正常人群和患病人群中具有类似的差异，在精神分裂症患者家庭中以符合主基因效应的方式分离。这些发现表明，该表型适用于连锁分析。为了增加样本的均质性和遗传负载量，将使用两种方法。首先(目标1)，将从多个受影响的家庭(2个或更多患有精神分裂症的家庭成员)收集扩展的家系。其次(目标2)，将通过利用精神分裂症先证者发病年龄非常早的家庭寻求增加遗传负荷，这些家庭的发病年龄在12岁或以下。将使用能够检测数量性状的遗传效应的方法来评估两组中的连锁。

DESCRIPTION: (provided by applicant): This is the third submission of this R01 proposal. The aims of this proposal are to perform a genomewide scan looking for linkage to a schizophrenia-associated endophenotype, an elevated frequency of leading saccades during a smooth pursuit eye movement (SPEM) task. SPEM abnormalities have been associated with schizophrenia for almost 100 years, and have been suggested as a potential marker of genetic risk for schizophrenia for over 20 years. Over the last several years, we have focused on identifying the component(s) of SPEM most specific to schizophrenia and most sensitive to presumed genetic risk. An elevated frequency of leading saccades during a SPEM task appears to be a sensitive and specific component of SPEM function. Elevated frequency of leading saccades is more common in individuals with schizophrenia than in the general population or in individuals with attention deficit/hyperactivity disorder, autism, or bipolar disorder; is more common in relatives of individuals with schizophrenia; appears to sort with presumed genetic risk for schizophrenia; and is usable from 6-80 years of age. Additionally, elevated leading saccade frequency is tri-modally distributed in the general population, has a similar variance in normal and affected populations, and segregates in families with schizophrenia in a manner consistent with a major gene effect. These findings suggest that this phenotypc is appropriate for linkage analysis. To increase the homogeneity and genetic loading of the sample, two approaches will be used. First (aim #1), extended pedigrees will be gathered from multi-affected families (2 or more family members with schizophrenia). Second (aim #2), increased genetic loading will be sought by utilizing families in which the schizophrenic probands have very early ages of onset, at age 12 years or younger. Linkage in both groups will assessed using methods capable of detecting genetic effects on quantitative traits.