MRI Studies of Folate-Related Genes, Diet, and Development: Promise for Psychosis

描述（申请人提供）：叶酸缺乏与精神分裂症的流行病学、基因组学和神经影像学研究有关。精神分裂症患者表现出与阴性症状严重程度相关的低血液叶酸水平，这种模式受到叶酸相关基因变异的强烈影响。我们小组最近的两项临床试验证明了叶酸补充剂对阴性症状的益处，但仅限于携带先前涉及的遗传变异的患者。我们还发现，在精神分裂症患者和健康个体中，叶酸相关基因对额顶叶控制网络内功能和结构MRI测量的影响一致。这项工作表明，（1）叶酸相关基因在精神分裂症中发挥重要的临床作用，与治疗反应有关，（2）这些基因影响精神分裂症治疗难治性方面的大脑系统。然而，叶酸代谢途径中遗传变异对大脑的影响仍然没有完全确定，膳食叶酸摄入量与大脑结构和功能之间的关系也是如此。此外，重要的是， 补充叶酸对精神分裂症的临床益处相对较小，即使是在携带易感基因变异的个体中。早期暴露于叶酸增加，包括在神经发育期间，可能会为高危个体带来更大的益处。事实上，最近的研究表明，在怀孕早期增加母亲叶酸摄入量可以降低自闭症的风险，特别是在叶酸代谢途径中具有低功能遗传变异的母亲中。这项针对健康成年人和青少年的研究将极大地扩展我们对叶酸如何影响大脑的理解，作为开发改进的叶酸干预措施的前奏。我们将集中在结构和功能的措施，在额顶叶控制系统是一贯异常的精神分裂症，并已绑定到叶酸相关基因。对于目标1，我们将利用现有的大量MRI数据和DNA（> 3，300名受试者）对整个叶酸代谢途径的遗传变异进行新的、基于多基因评分的分析。在目标2中，我们将招募一系列多基因评分的个体，以确定叶酸摄入量如何影响高分辨率结构和功能MRI指标。使用相同的MRI测量，目标3将利用最近的大规模公共卫生干预来检查子宫内叶酸暴露对两个年龄匹配的健康青少年队列的影响：一组将在1998年实施强制性叶酸强化谷物产品之前怀孕，另一组将在此干预后怀孕。这种多层次的方法将使我们能够全面评估叶酸对大脑影响的基因组（目标1），环境（目标2）和神经发育（目标3）方面，无论是单独还是相互结合。这项工作可能对使用有针对性的高剂量叶酸增加作为预防策略具有重要意义，特别是在精神分裂症高风险的年轻人中，甚至是怀孕前。

DESCRIPTION (provided by applicant): Folate deficiency has been implicated in epidemiologic, genomic, and neuroimaging studies of schizophrenia. Patients with schizophrenia exhibit low blood folate levels that correlate with negative symptom severity, a pattern that is strongly influenced by variation in folate-related genes. Two recent clinical trial by our group demonstrated a benefit of folate supplementation for negative symptoms, but only among patients who carried the previously implicated genetic variants. We have also seen consistent effects of folate-related genes on functional and structural MRI measures within the frontoparietal control network, in both patients with schizophrenia and healthy individuals. This work suggests that (1) folate-related genes exert important clinical effects in schizophrenia that are relevant to treatment response, and (2) these genes influence brain systems that underlie treatment-refractory aspects of schizophrenia. However, the effects of genetic variation across the folate metabolic pathway on the brain remain incompletely characterized, as does the relationship between dietary folate intake and brain structure and function. Also, importantly, the clinical benefit of folate supplementation in schizophrenia was relatively modest, even among individuals who carried predisposing genetic variants. Earlier exposure to folate augmentation, including during neurodevelopment, may confer a stronger benefit for at-risk individuals. Indeed, recent studies suggest that increased maternal folate intake early in pregnancy can reduce the risk of autism, especially among mothers who have low-functioning genetic variants in the folate metabolic pathway. The proposed study of healthy adults and adolescents will greatly extend our understanding of how folate influences the brain, as a prelude to developing improved folate-based interventions. We will focus on structural and functional measures in the frontoparietal control system that are consistently abnormal in schizophrenia, and that have been tied to folate-related genes. For Aim 1, we will leverage a large, existing collection of MRI data and DNA (>3,300 subjects) to conduct novel, polygene-score based analyses of genetic variation throughout the folate metabolic pathway. In Aim 2, we will recruit individuals across a range of polygene scores to determine how folate intake influences high-resolution structural and functional MRI indices. Using the same MRI measures, Aim 3 will leverage a recent large-scale public health intervention to examine effects of in utero folate exposure in two age-matched cohorts of healthy adolescents: one group will have gestated before mandatory folate fortification of grain products was implemented in 1998, and the other will have gestated after this intervention. This multi-tiered approach will allow us to comprehensively evaluate genomic (Aim 1), environmental (Aim 2), and neurodevelopmental (Aim 3) aspects of folate effects on the brain, both separately and in combination with each other. This work could have important implications for the use of targeted, high-dose folate augmentation as a preventative strategy, especially among young individuals at high risk for schizophrenia, or even pre-conception.