Psychosis risk variants and cognitive control in clinically-referred youth

临床转介青少年的精神病风险变异和认知控制

• 批准号: 9059185
• 负责人: ALYSA E DOYLE
• 金额: $ 8.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059185
• 关键词: Alleles; Behavioral Genetics; Biology; Calcium Channel; Categories; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Collaborations; Collection; Communication; Complex; Data; Data Analyses; Data Collection; Data Set; Development; Diagnosis; Diagnostic; Dissection; Early Intervention; Evaluation; Family Study; Fostering; Funding; General Hospitals; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Risk; Genetic study; Genome Scan; Genotype; Goals; Health; Human Genetics; Impaired cognition; Impairment; Individual; Institutes; Investigation; Leadership; Link; Literature; Maintenance; Maps; Massachusetts; Measurable; Measures; MicroRNAs; Modeling; Molecular Genetics; Mutation; National Institute of Mental Health; Patients; Pattern; Performance; Phenotype; Predisposition; Prospective Studies; Psychiatry; Psychopathology; Psychotic Disorders; Research; Research Domain Criteria; Risk; Role; Sampling; Short-Term Memory; Signal Transduction; Structure; Synapses; Taxonomy; Testing; Twin Multiple Birth; Twin Studies; Variant; Work; Youth; base; biological systems; cognitive control; cognitive system; cognitive testing; cohort; disorder risk; effective intervention; follow-up; genetic variant; genome-wide; improved; neuropsychiatry; novel; programs; response; risk variant; severe mental illness; synaptic function; targeted treatment; trait; voltage

 DESCRIPTION (provided by applicant): Family, twin and prospective studies of psychosis provide strong but indirect evidence that impaired cognitive control is a manifestation of underlying genetic risk for this devastating form of psychopathology. Findings from recent, large-scale genomewide studies now offer the chance to extend this line of investigation directly to molecular genetic data. In response to PAR-14-007, we aim to capitalize on an available data set to pursue such analyses. Specifically, we will examine emerging psychosis-relevant genetic variants in relation to three constructs (working memory, inhibition and goal maintenance) that overlap with the domain of cognitive control, as defined in NIMH's Research Domain Criteria (RDoC). RDoC was developed precisely to encourage investigation of genetic advances such as these in relation to dimensional traits unconstrained by conventional diagnoses. Currently, we are near-completion of a pilot clinical research cohort of youth uniquely-suited to such investigation. In this sample, subjects are ascertained, regardless of diagnosis, as consecutive referrals for neuropsychiatric evaluations that include cognitive assessment. Using these data in this R03, we will test the hypothesis that, across diagnostic boundaries, a greater burden of common genetic variants that confer risk for psychosis associates with greater impairment in our three aspects of cognitive control. Second, we will test the hypothesis that variation in psychosis-relevant gene sets that support synaptic communication and plasticity will similarly associate with variation in these aspects of cognitive control. Based on our preliminary data, we expect that our findings will advance the core tenets of RDoC and suggest that genetic risk for psychosis operates beyond conventional diagnostic boundaries and can be detected in relation to cognitive control phenotypes measurable in youth. These data will further help to link these cognitive constructs to particular biological systems. As such, these data will allow us to refine cognitive phenotypes we investigate as we enlarge our sample (under separate funding) and work to improve pathophysiologically-based models of the unfolding of genetic risk for psychosis. Eventually, such findings could facilitate earlier and more effective interventions in youth at risk for severe neuropsychiatric illness.

 描述（由申请人提供）：精神病的家族、双胞胎和前瞻性研究提供了强有力但间接的证据，证明认知控制受损是这种毁灭性精神病理学形式的潜在遗传风险的表现。最近的大规模全基因组研究的结果现在提供了将这一调查路线直接扩展到分子遗传数据的机会。作为对PAR-14 - 007的回应，我们的目标是利用现有的数据集进行此类分析。具体来说，我们将研究与认知控制领域重叠的三个结构（工作记忆，抑制和目标维持）相关的新出现的精神病相关遗传变异，如NIMH的研究领域标准（RDoC）中所定义的。RDoC的开发正是为了鼓励研究遗传学的进步，例如与不受传统诊断限制的尺寸性状有关的遗传学进步。目前，我们即将完成一项非常适合此类调查的青年试点临床研究队列。在这个样本中，受试者被确定，无论诊断，作为连续转介的神经精神评价，包括认知评估。使用本R03中的这些数据，我们将检验以下假设：在诊断边界上，赋予精神病风险的常见遗传变异的更大负担与我们认知控制的三个方面的更大损害相关。其次，我们将测试的假设，即支持突触沟通和可塑性的精神病相关基因集的变化将同样与认知控制的这些方面的变化。根据我们的初步数据，我们预计我们的研究结果将推进RDoC的核心原则，并表明精神病的遗传风险超出了传统的诊断界限，并且可以在青年中可测量的认知控制表型中检测到。这些数据将进一步帮助将这些认知结构与特定的生物系统联系起来。因此，这些数据将使我们能够改进我们在扩大样本（在单独的资金支持下）时调查的认知表型，并致力于改善精神病遗传风险展开的病理生理学模型。最终，这些发现可以促进对有严重神经精神疾病风险的青年进行更早和更有效的干预。