Schizophrenia genetics, neural and cognitive phenotypes, and social functioning

描述（由申请人提供）：社会功能缺陷一直与精神分裂症和精神分裂症风险有关。研究已经揭示了健康个体中影响社会功能的特定神经和认知机制，并且在精神分裂症患者及其未受影响的一级亲属中发现了其中一些机制的异常[1-3]。这表明，精神分裂症的遗传风险可能表现为这些基本神经和认知机制的变异，即使在没有精神障碍的个体中也是如此。最近的遗传发现工作已经开始揭示精神分裂症的遗传结构，产生了(1)估计精神分裂症多基因风险的方法，或整个基因组中单核苷酸多态性变异引起的总风险[4]，以及(2)与精神分裂症相关的特定遗传变异，即使在全基因组统计校正[5]之后也是如此。有了这些新发现，就有了新的机会来确定从遗传风险到最终可能导致精神分裂症的神经功能、信息处理和行为缺陷的潜在途径。在这里，我关注的是最近发现的遗传预测因子与与社会功能相关的中间神经和认知表型之间的关系。目前的建议旨在回答以下问题：(1)与社会功能相关的中间神经/认知表型的变异有多少可以用单核苷酸多态性的变异来解释？(2)精神分裂症的多基因风险是否可以预测社会功能表型的变化？(3)最近发现的精神分裂症遗传风险变异能否预测社会功能表型的变化？拟议的研究使用中间表型作为一种获得从验证遗传风险因素到精神障碍的机制的牵引的方式。拟议的研究可能通过遗传风险因素对神经结构和社会认知的特定方面的作用，确定遗传风险因素影响患精神分裂症风险的途径。这些特定途径的识别将为精神分裂症的发病机制提出新的假设，并为治疗、干预和进一步研究提供潜在的靶点。

DESCRIPTION (provided by applicant): Deficits in social functioning are consistently linked with schizophrenia and schizophrenia risk. Research has uncovered specific neural and cognitive mechanisms that contribute to social functioning in healthy individuals, and abnormalities in some of these mechanisms have been identified in both schizophrenia patients and their unaffected first-degree relatives [1-3]. This suggests that genetic risk for schizophreni may manifest in terms of variations in these basic neural and cognitive mechanisms, even in individuals without a mental disorder. Recent genetic discovery efforts have begun to unravel the genetic architecture of schizophrenia, yielding (1) methods for estimating schizophrenia polygenic risk, or the aggregate risk arising from variations in single-nucleotide polymorphisms across the entire genome [4], and (2) specific genetic variants that are associated with schizophrenia, even after genome-wide statistical correction [5]. With these new discoveries, there are new opportunities for identifying potential pathways leading from genetic risk to deficit in neural function, information processing, and behavior that ultimately may lead to schizophrenia. Here, I focus on the relationship between recently identified genetic predictors and intermediate neural and cognitive phenotypes related to social functioning. The current proposal aims to answer the following questions: (1) How much of the variation in intermediate neural/cognitive phenotypes related to social functioning can be explained by variations in single-nucleotide polymorphisms? (2) Does estimated polygenic risk for schizophrenia predict variations in social functioning phenotypes? (3) Do recently identified schizophrenia genetic risk variants predict variations in social functioning phenotypes? The proposed research uses intermediate phenotypes as a way of gaining traction on the mechanisms that lead from validated genetic risk factors to mental disorders. The proposed research may enable the identification of pathways through which genetic risk factors influence risk for developing schizophrenia, through their action on particular aspects of neural architecture and social cognition. Identification of these specific pathways will suggest new hypotheses for the pathogenesis of schizophrenia and offer potential targets for treatment, intervention, and further research.