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成功的学术生涯。该培训补助金将使申请人能够制定一项研究计划，重点是将遗传脆弱性模型应用于精神分裂症难治性阴性症状研究的转化研究。在寻找精神分裂症潜在的生物学机制中，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，即快感缺乏，或个体对社会和身体刺激的快乐或兴趣程度，与精神分裂症的遗传易感性有关，并与精神分裂症谱系障碍前驱易感性的差异有关。在多项纵向研究中，快感缺乏是任何自我报告的精神分裂症谱系障碍的典型症状的最佳预测因素。它也是唯一一个自我报告的、能够始终将精神分裂症患者的一级亲属与对照组区分开来的典型特征。在精神分裂症患者中，快感缺乏表明疾病的预后较差，功能结果较差。 尽管它作为一种内表型的重要性，但目前尚不清楚快感缺失如何与精神分裂症的神经生物学底物直接相关。目前，有证据表明，快感缺失与情绪处理的差异有关，特别是与积极情感强度降低有关。然而，还没有人在患者或其一级亲属中研究这种关联。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病的遗传易感性有关。一项先前的研究发现，具有Val 158 Met儿茶酚-O-甲基转移酶（COMT）基因高活性多态性的亲属，负责抑制多巴胺，自我报告的快感缺乏水平较高。其次，现在有证据表明，快感缺失可能与人类精神分裂症1（DISC 1）基因表达中断有关，DISC 1基因影响海马功能。然而，在精神分裂症患者的一级亲属中，快感缺乏与候选单核苷酸多态性的可能关联很少被研究。重要的是要检查快感缺失和内表型-基因型关联的情绪处理，以更好地理解这种治疗难治性症状。NIMH目前正在寻求统一先进的统计方法和增强测量，这将有助于减少异质性和进一步寻找精神病理学的遗传基础。本研究试图达到这一目的。

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.