MRI DNA Biomarkers for Neuropsychiatric Disease

描述（由申请人提供）：精神分裂症（SZ）是一种严重的衰弱性精神疾病。它是高度遗传的，在单卵双胞胎中的一致率为50-80%，并有大量的家族聚集性。精神病学中基于现象学的诊断系统具有严重的局限性，导致分类缺乏明确的界限和生物学基础。关于SZ，在许多方面与其他疾病有广泛的重叠，包括症状、神经生理学、脑成像、认知和药物治疗。我们的最终目标是开发一种名为“Phyziotype”的新产品，该产品将通过评估遗传因素对该疾病的实质性贡献（50-80%）来显著改善SZ的诊断。Phyziotype由单核苷酸多态性（SNP）的多基因集合组成，其用生物数学算法解释，可以预测SZ的发作，更清楚地描述其与相关疾病的诊断，并区分潜在的病因亚型。该第二阶段计划涉及发现形成Phyziotype基础的MRI DNA标记。通过基于常规精神病表型的关联研究发现预测性生物标志物受到临床混杂因素和个体标志物的小效应大小的限制。我们假设，“内表型”，已知的亚临床脆弱性表型，更强烈地与个别基因比临床观察，并提供了一个强大的工具来发现预测性生物标志物。脑功能磁共振成像（fMRI）是一种多功能的技术，用于测量重要的精神病内表型。本项目将利用fMRI内表型与全基因组SNP阵列进行关联筛选，以确定与SZ诊断相关的MRI DNA标记。这些生物标志物将促进我们对遗传风险因素和神经生理学的理解，并可能通过改进精神病诊断来刺激药物开发的新方法。这个第二阶段计划将Genomas的生理基因组学能力与哈特福德医院生活研究所的戈弗雷·皮尔逊博士的领先功能磁共振成像研究以及MIND研究所和新墨西哥州大学的文森特·卡尔霍恩博士的先进神经信息学能力相结合。随着生活研究所和MIND研究网络的丰富患者人群的开放，该团队已经将神经成像和生理基因组学整合为精神疾病分子分析的新平台，并在“人脑映射”和“生物医学工程年鉴”上发表了两篇论文。该II期SBIR计划将这些研究扩展至包括500名SZ患者和250名健康对照。所有参与者将使用全基因组阵列进行1，072，820个SNP和13，298个拷贝数变异的基因分型。将使用fMRI内表型的生理基因组学分析的集中和无假设模式来发现SZ的MRI DNA标记。将开发包含多个SNP的生理基因组模型作为Phyziotype系统的研究原型。精神分裂症（SZ）是一种严重的精神疾病，目前困扰着240万美国成年人。第二阶段计划将利用功能磁共振成像内表型和全基因组SNP筛选，以确定MRI DNA标记相关的精神分裂症。MRI DNA标记物最终将允许开发完善精神疾病临床诊断的系统，并可能预测个体对精神分裂症和其他疾病的易感性。实际诊断产品的开发将在第三阶段进行，作为FDA批准的个性化心理健康诊断系统。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severely debilitating mental illnesses. It is highly heritable, with concordance rates of 50-80% in monozygotic twins and substantial familial clustering. Phenomenology-based diagnostic systems in psychiatry have serious limitations resulting in classifications lacking clear boundaries and biological basis. With respect to SZ, there is extensive overlap with other disorders on many dimensions, including symptoms, neurophysiology, brain imaging, cognition, and pharmacotherapy. Our eventual goal is to develop a novel product termed "Phyziotype", which will substantially improve the diagnosis of SZ by accessing the substantial contribution (50-80%) of genetic factors to the disease. The Phyziotype consists of a multi-gene ensemble of single nucleotide polymorphisms (SNPs) which, interpreted with a biomathematical algorithm, may predict the onset of SZ, more clearly delineate its diagnosis from related disorders, and distinguish between potential etiological subtypes. This Phase II Program is concerned with the discovery of the MRI DNA markers that form the foundation of the Phyziotype. The discovery of predictive biomarkers through association studies based on conventional psychiatric phenotypes has been limited by clinical confounders and the small effect sizes for individual markers. We hypothesize that "endophenotypes", known subclinical vulnerability phenotypes, are more strongly associated to individual genes than clinical observations, and provide a powerful tool to discover predictive biomarkers. Functional magnetic resonance imaging (fMRI) of the brain is a versatile technique for measuring important psychiatric endophenotypes. This Program will utilize fMRI endophenotypes for association screening with total genome SNP arrays to identify MRI DNA markers relevant to the diagnosis of SZ. These biomarkers will advance our understanding of genetic risk factors and neurophysiology and may stimulate novel approaches to pharmaceutical development by refining psychiatric diagnosis. This Phase II program integrates the substantial physiogenomic capabilities of Genomas with the leading fMRI research of Dr. Godfrey Pearlson of Hartford Hospital's Institute of Living and the advanced neuroinformatics capabilities of Dr. Vincent Calhoun at the MIND Institute and the University of New Mexico. With ready access to a rich patient population at the Institute of Living and the MIND Research Network, the team has already integrated neuroimaging and physiogenomics as a novel platform for molecular analysis of mental illness, leading to two publications in 'Human Brain Mapping' and 'Annals of Biomedical Engineering'. This Phase II SBIR Program extends these studies to include 500 SZ patients and 250 healthy controls. All participants will be genotyped for 1,072,820 SNPs and 13,298 copy number variants using total genome arrays. Focused and Hypothesis-free Modes of physiogenomic analysis with fMRI endophenotypes will be used to discover MRI DNA markers for SZ. Physiogenomic models incorporating multiple SNPs will be developed as research prototypes for a Phyziotype system. PUBLIC HEALTH RELEVANCE: Schizophrenia (SZ) is a severely debilitating mental illnesses, currently afflicting 2.4 million American adults. The Phase II program will utilize fMRI endophenotypes and total genome SNP screening to identify MRI DNA markers relevant to schizophrenia. MRI DNA markers will eventually allow the development of systems that refine the clinical diagnosis of mental illness and may predict the individual susceptibility to schizophrenia and other disorders. The development of the actual diagnostic product will be pursued during Phase III as an FDA-approved diagnostic system for personalized mental health.