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

精神分裂症患者一级亲属的内表型-基因型关联

• 批准号: 8139702
• 负责人: Anna R. Docherty
• 金额: $ 3.05万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139702
• 关键词: Accounting; Address; Affect; Affective Symptoms; Alleles; Anhedonia; Behavioral; Behavioral Genetics; Biological; Catechols; Clinical Psychology; Development; Diagnosis; Disease; Dopamine; Emotions; Family member; Finland; First Degree Relative; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Grant; Heterogeneity; Hippocampus (Brain); Human; Individual; Intervention; Longitudinal Studies; Measurement; Measures; Mediating; Mental Depression; Methodology; Modeling; National Institute of Mental Health; Neurobiology; Outcome; Pathogenesis; Patient Self-Report; Patients; Pharmacological Treatment; Phenotype; Prevention; Process; Psychopathology; Psychotic Disorders; Refractory; Regulation; Relative (related person); Reporting; Research; Risk; Schizophrenia; Schizotypal Personality Disorder; Single Nucleotide Polymorphism; Stimulus; Symptoms; Time; Training; Transferase; Transferase Gene; Translational Research; base; behavior measurement; career; cell motility; cohort; endophenotype; experience; functional outcomes; genome wide association study; improved; interest; neurophysiology; outcome forecast; pleasure; positive emotional state; positive mood; programs; psychologic; social; trait; transmission process; university student

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.

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。这项培训补助金将使申请人能够发展一个研究项目，重点是将遗传易感性模型应用于精神分裂症治疗难治性阴性症状的研究。在寻找精神分裂症的潜在生物学机制中，针对内表型的关联研究的需求越来越大。有证据表明，一种内表型，快感缺乏，或个体报告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，并且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，快感缺乏症是任何自我报告的分裂型症状中最能预测精神分裂症谱系障碍的。这也是唯一一种自我报告的分裂型特征，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。在精神分裂症患者中，快感缺乏表明疾病预后较差，功能预后较差。尽管它作为一种内表型很重要，但尚不清楚快感缺乏如何与精神分裂症的神经生物学底物直接相关。目前，有证据表明快感缺乏症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，还没有人研究过患者或他们的一级亲属之间的这种联系。此外，有证据表明，在一级亲属中存在快感缺乏的遗传基础。首先，异常的多巴胺传递可能与积极情绪的加工有关，并与精神分裂症的症状和对精神病的遗传易感性有关。先前的一项研究发现，Val158Met儿茶酚-o-甲基转移酶（COMT）基因（负责抑制多巴胺）具有高活性多态性的亲属，自我报告的快感缺乏症水平更高。其次，现在有证据表明快感缺乏可能与人类精神分裂症1基因表达紊乱有关，该基因影响海马功能。然而，快感缺乏症与候选单核苷酸多态性的可能关联很少在精神分裂症患者的一级亲属中进行检查。为了更好地理解这种治疗难治性症状，检查快感缺乏症的情绪加工和内表型-基因型关联是很重要的。NIMH目前正在寻求先进统计方法的统一和测量的增强，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。本研究试图解决这一问题。

项目成果

Best practices: The electronic medical record is an invaluable clinical tool: let's start using it.

最佳实践：电子病历是一种非常宝贵的临床工具：让我们开始使用它。

• DOI: 10.1176/appi.ps.201300272
• 发表时间: 2013
• 期刊: Psychiatric services (Washington, D.C.)
• 作者: Vrieze,ScottI;Docherty,Anna;Thuras,Paul;Arbisi,Paul;Iacono,WilliamG;Sponheim,Scott;Erbes,ChristopherR;Siegel,Wayne;Leskela,Jennie
• 通讯作者: Leskela,Jennie