Endophenotype-genotype associations in first-degree relatives of people with schi

描述(由申请人提供)：申请人的长期目标是在临床心理学方面取得成功的学术生涯。这笔培训赠款将使申请者能够制定一项研究计划，重点是转化性研究，将遗传脆弱性模型应用于精神分裂症治疗难治性阴性症状的研究。在寻找精神分裂症潜在的生物学机制方面，越来越需要针对内表型的关联研究。有证据表明，一种内在表型，快感缺乏症，即一个人报告的对社会和身体刺激的愉悦或兴趣的程度，与精神分裂症的遗传易感性有关，与精神分裂症谱系障碍的前驱易感性的差异有关。在多项纵向研究中，快感缺乏对任何自我报告的分裂型症状的精神分裂症谱系障碍的预测作用最大。这也是唯一自我报告的分裂型特征，可以一致地区分精神分裂症患者的一级亲属和对照组。在精神分裂症患者中，快感缺乏意味着疾病预后较差，功能结果较差。尽管快感缺乏症作为一种内表型很重要，但它如何与精神分裂症的神经生物学底物直接相关还不清楚。目前，有证据表明快感缺失与情绪处理的差异有关，特别是与积极情绪强度的降低有关。然而，还没有人研究患者或他们的一级亲属之间的这种联系。此外，有证据表明，一级亲属中存在快感缺失的遗传基础。首先，异常的多巴胺传递可能与积极情绪的处理有关，并与精神分裂症的症状和精神疾病的遗传易感性有关。先前的一项研究发现，具有Val158Met儿茶酚-o-甲基转移酶(COMT)基因高活性多态的亲属，负责抑制多巴胺，有更高的自我报告的快感缺乏水平。其次，现在有证据表明，快感缺乏可能与人类精神分裂症-1中断(DISC1)基因表达有关，DISC1基因影响海马体功能。然而，在精神分裂症患者的一级亲属中，很少研究快感缺失与候选单核苷酸多态的可能关联。重要的是要同时检查快感缺失的情绪处理和内表型-基因相关性，以更好地了解这种治疗难治的症状。NIMH目前正在寻求先进的统计方法和测量方面的改进的统一，这将有助于减少异质性，并进一步探索精神病理学的遗传基础。这项研究试图解决这一目标。 公共卫生相关性：目前的研究有可能为精神分裂症患者的预防和治疗提供信息。了解精神分裂症遗传易感性中特定的遗传机制与亚临床分裂型症状之间的关系，以及阴性症状与情感加工之间的关系，可能会对精神分裂症的心理和药物治疗产生影响。此外，了解这些机制可能有助于改善精神分裂症患者的功能结果，因为快感缺失与功能结果密切相关。

DESCRIPTION (provided by applicant): The applicant's long-term goal is a successful academic career in clinical psychology. This training grant will enable the applicant to develop a program of research focusing on translational research applying models of genetic vulnerability to research on the treatment-refractory negative symptoms of schizophrenia. There is growing need for association studies targeting endophenotypes in the search for the underlying biological mechanisms of schizophrenia. There evidence that one endophenotype, anhedonia, or the extent to which an individual reports pleasure or interest in social and physical stimuli, is associated with genetic liability to schizophrenia, and with differences in prodromal vulnerability to schizophrenia-spectrum disorders. Anhedonia has been most predictive of schizophrenia-spectrum disorders of any self-reported schizotypal symptom in multiple longitudinal studies. It has also been the only self-reported schizotypal trait to consistently differentiate first-degree relatives of people with schizophrenia from controls. In people with schizophrenia, anhedonia indicates poorer prognosis of the illness and poorer functional outcome. Despite its importance as an endophenotype, it has been unclear how anhedonia might directly relate to the neurobiological substrates of schizophrenia. Currently, there is evidence that anhedonia is associated with differences in emotion processing, specifically with decreased positive affect intensity. However, no one has yet studied this association in patients or their first-degree relatives. In addition, there is evidence for genetic underpinnings of anhedonia in first-degree relatives. First, aberrant dopamine transmission may relate to the processing of positive emotion, and is implicated in symptoms of schizophrenia and in genetic vulnerability to psychosis. One prior study has found that relatives with a high-activity polymorphism of the Val158Met catechol-o-methyl-transferase (COMT) gene, responsible for the inhibition of dopamine, have higher levels of self-reported anhedonia. Second, there is now evidence that anhedonia may be related to disrupted-in- schizophrenia-1 (DISC1) gene expression in humans, a gene that influences hippocampal function. However, possible associations of anhedonia with candidate single nucleotide polymorphisms have rarely been examined in first-degree relatives of people with schizophrenia. It is important to examine both emotion processing in anhedonia and endophenotype-genotype associations, to develop a better understanding of this treatment-refractory symptom. NIMH is currently seeking the unification of advanced statistical methodologies and enhancements in measurement that will facilitate the reduction of heterogeneity and further the search for the genetic basis of psychopathology. This study attempts to address that aim. PUBLIC HEALTH RELEVANCE: The current research has the potential to inform both prevention efforts and treatment for people with schizophrenia. Understanding the relationship between specific genetic mechanisms and subclinical schizotypal symptoms in first-degree family members, as well as the relationship between negative symptoms and affective processing in genetic liability to schizophrenia may impact both psychological and pharmacological treatments for schizophrenia. Moreover, understanding these mechanisms may help to improve functional outcome in people with schizophrenia, since anhedonia has been strongly associated with functional outcome.