Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia

描述（由申请人提供）：这是一份申请NIMH患者导向研究职业发展奖（K23）的申请，标题为“MTHFR基因型对精神分裂症患者额叶功能障碍的贡献”。虽然精神分裂症（Sz）是一种强烈的遗传性疾病，但由于其相对较小的个体对临床表型的贡献，对风险赋予基因的研究一直受到阻碍。近年来，Sz神经成像专家试图通过测量风险等位基因对大脑生理水平的影响，而不是行为水平，来放大风险等位基因的信号。这种方法产生的结果是可靠的和内部一致的，但在很大程度上与细胞和分子病理生理学脱节，更重要的是，与药物发现脱节。候选人的兴趣是成像遗传学的全部转化潜力，作为连接Sz认知障碍的基本机制和新治疗方法的中转站。为此，该候选人之前和提议的工作涉及Sz中涉及的两个生化途径-叶酸和多巴胺代谢-交集的功能遗传变异如何促进前额叶和工作记忆功能。在回顾性研究中，候选人将MTHFR C677T多态性与Sz患者的工作记忆和前额叶功能障碍联系起来。这些影响通过与COMT Val158Met基因型的诊断特异性相互作用进一步放大，表明MTHFR T等位基因可能加剧Sz的前额叶多巴胺缺乏。这项计划中的研究是对基因匹配的Sz患者和健康对照者进行前瞻性功能磁共振成像（fMRI）调查，将试图验证和微调MTHFR对Sz工作记忆的有害影响机制。MTHFR和COMT基因型将映射到工作记忆维持和时间更新组件中的前额叶功能，使用与前额叶多巴胺信号相关的任务。拟议的研究计划、教学课程以及导师、顾问和其他顾问的个人指导将促进候选人发展成为一名独立的临床研究者，研究Sz基因效应的功能神经影像学。公共卫生相关性：精神分裂症患者认知障碍的有效治疗方法仍然很少。希望这些研究将为开发基于个体遗传变异及其对脑功能的下游影响的新的更有效的认知增强策略奠定基础。我们感兴趣的基因MTHFR和COMT参与了两种与精神分裂症有关的相关生化途径，并且可以用目前正在开发的药物进行有针对性的干预。

DESCRIPTION (provided by applicant): This is an application for an NIMH Patient Oriented Research Career Development Award (K23) entitled "Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia." Although schizophrenia (Sz) is a strongly heritable disorder, the search for risk-conferring genes has been hindered by their relatively small individual contributions to clinical phenotypes. In recent years, Sz neuroimagers have attempted to amplify the signal of risk alleles by measuring their effects on the level of brain physiology, rather than behavior. This approach has yielded results that are robust and internally consistent, but largely disconnected from cellular and molecular pathophysiology, and more importantly, to drug discovery. The candidate's interest is in the full translational potential of imaging-genetics, as a way station connecting basic mechanisms and novel treatments for cognitive impairment in Sz. Toward this end, the candidate's previous and proposed work concerns how functional genetic variants at the intersection of two biochemical pathways implicated in Sz - folate and dopamine metabolism - contribute to prefrontal and working memory function. In retrospective studies, the candidate has associated the MTHFR C677T polymorphism with working memory and prefrontal dysfunction in Sz patients. These effects were further magnified through a diagnostically specific interaction with COMT Val158Met genotype, suggesting that the MTHFR T allele may exacerbate prefrontal dopamine deficiencies in Sz. The planned study, a prospective functional magnetic resonance imaging (fMRI) investigation of genetically matched Sz patients and healthy controls, will attempt to validate and fine-tune the proposed mechanism of deleterious MTHFR effects on working memory in Sz. MTHFR and COMT genotype will be mapped to prefrontal function during maintenance and temporal updating components of working memory, using tasks that have been tied to prefrontal dopamine signaling. The proposed research plan, didactic courses, and individual instruction from mentors, advisors, and other consultants will foster the candidate's development into an independent clinical investigator in the functional neuroimaging of gene effects in Sz. PUBLIC HEALTH RELEVANCE: There remain few effective treatments for cognitive impairment in schizophrenia. It is hoped that these Studies will lay a foundation for the development of new and more efficient cognitive enhancement strategies, based on individual genetic variation and its downstream effects on brain function. The genes of interest, MTHFR and COMT, contribute to two related biochemical pathways that have been implicated in schizophrenia, and are that amenable to targeted interventions with drugs currently in development.