MRI DNA Biomarkers for Neuropsychiatric Disease

描述（由申请人提供）：精神分裂症（SZ）是一种严重衰弱的精神疾病。它具有高度遗传性，同卵双胞胎的一致性率为50-80%，并具有大量的家族聚类。基于现象学的精神病学诊断系统存在严重的局限性，导致分类缺乏明确的界限和生物学基础。就SZ而言，在症状、神经生理、脑成像、认知和药物治疗等许多方面与其他疾病有广泛的重叠。我们的最终目标是开发一种名为“Phyziotype”的新产品，该产品将通过获取对SZ疾病的重大贡献（50-80%）遗传因素来大大提高SZ的诊断。该Phyziotype由单核苷酸多态性（snp）的多基因集合组成，通过生物数学算法进行解释，可以预测SZ的发病，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。这个II期项目关注的是发现形成植型基础的MRI DNA标记。通过基于传统精神病学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效应较小的限制。我们假设“内表型”，即已知的亚临床易感性表型，与个体基因的相关性比临床观察结果更强，并为发现预测性生物标志物提供了强大的工具。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内表型。该项目将利用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学诊断来刺激药物开发的新方法。该二期项目将Genomas的生理基因组学能力与Hartford医院生命研究所的Godfrey Pearlson博士的领先fMRI研究以及MIND研究所和新墨西哥大学的Vincent Calhoun博士的先进神经信息学能力相结合。有了生活研究所和MIND研究网络丰富的患者群体，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《人类大脑图谱》和《生物医学工程年鉴》上发表了两篇文章。二期SBIR项目将这些研究扩展到500名SZ患者和250名健康对照者。所有参与者将使用总基因组阵列对1,072,820个snp和13,298个拷贝数变异进行基因分型。利用fMRI内表型进行生理基因组分析的集中和无假设模式将用于发现SZ的MRI DNA标记。包含多个snp的生理基因组模型将被开发为Phyziotype系统的研究原型。公共卫生相关性：精神分裂症（SZ）是一种严重的使人衰弱的精神疾病，目前折磨着240万美国成年人。II期项目将利用fMRI内表型和全基因组SNP筛选来鉴定与精神分裂症相关的MRI DNA标记。核磁共振DNA标记最终将允许系统的发展，以完善精神疾病的临床诊断，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.