Genomic Biomarkers for Neuropsychiatric Illnesses

神经精神疾病的基因组生物标志物

• 批准号: 8044768
• 负责人: Mark David Brennan
• 金额: $ 37.11万
• 依托单位: SUREGENE, LLC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-26 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044768
• 关键词: African American; Algorithms; Basic Science; Biological; Biological Markers; Bipolar Disorder; Caucasians; Caucasoid Race; Classification; Clinical; Communities; Complex; DNA Resequencing; Data; Data Set; Diagnosis; Diagnostic; Differential Diagnosis; Dimensions; Disease; Family; Family health status; Family history of; Generations; Genes; Genetic; Genetic Counseling; Genetic Markers; Genetic Models; Genetic Polymorphism; Genetic Programming; Genetic screening method; Genome; Genomics; Genotype; Goals; Grant; Haplotypes; Health; Health Personnel; Individual; Legal patent; Medical; Mental disorders; Mutation; National Institute of Mental Health; Outcome; Patients; Penetrance; Pharmacogenetics; Phase; Phenotype; Positioning Attribute; Psychopathology; Psychotic Disorders; Public Domains; Research; Research Personnel; Resources; Risk; Sampling; Schizophrenia; Sensitivity and Specificity; Single Nucleotide Polymorphism; Technology; Testing; Variant; Work; Youth; base; case control; clinical application; cohort; cost effective; density; design; disorder control; disorder risk; disorder subtype; expectation; flexibility; genetic variant; high risk; improved; meetings; neuropsychiatry; next generation; novel; predictive modeling; proband; prospective; prototype; public health relevance; tool

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop validated, genetic biomarkers to aid in more accurate diagnosis and targeted treatment of schizophrenia and related neuropsychiatric illnesses, including bipolar disorder. In Phase I, SureGene demonstrated the feasibility of using specific dimensions of mental illness to discover novel genes and genetic variants that influence risk and impact the clinical presentation of these diseases. This project will build on first-generation genetic biomarkers in the form of single nucleotide polymorphisms (SNPs) and chromosomally-related associations of these polymorphisms called haplotypes. The Phase II project will further develop biomarkers for neuropsychiatric illnesses using a set of genes that meet stringent criteria for genetic replication. The project will develop products for research and clinical applications that combine biomarkers in these genes. The aims are 1) Develop a prototype AssureGeneTM array and data set for schizophrenia-spectrum disorders. SureGene will develop a flexible SNP genotyping product incorporating a high density of SNPs in approximately 200 genes and generate a detailed data set relating genotypes to phenotypes based on 2000 NIMH schizophrenia, bipolar, and control samples. A first-generation array and data set will be made available to the research community by the middle of Grant Year 2. A refined array and data set for prospective clinical applications will be completed by the end of Phase II. 2) Evaluate the utility of the AssureGeneTM test for differential diagnosis and for predicting progression to clinically defined psychosis. SureGene will develop genetic algorithms for the array for use in predicting dichotomous clinical outcomes. This Aim should provide a collective set of predictive models that can be evaluated on the basis of their sensitivity, specificity, and overall classification accuracy. 3) Develop and implement a flexible medical resequencing platform (ExonReadTM) for high priority genes. SureGene will develop a cost-effective "next generation" medical resequencing platform that can be used by the research community to evaluate the contribution of rare or spontaneous mutations in key genes contributing to psychopathology and clinical outcomes for neuropsychiatric illnesses. A prototype sequencing platform for research use will be completed in Grant Year 2. SureGene will apply ExonReadTM to a sample of African Americans and Caucasians with a family history of schizophrenia or bipolar disorder to establish baseline expectations and limitations of the product. The commercial potential for these products is significant. By targeting common variants, the AssureGeneTM array should have broad applicability in research and clinical settings, with both diagnostic and pharmacogenetic applications. The ExonReadTM platform will be a valuable, cost-effective tool for identifying rare or unique high penetrance mutations expected in familial cases of neuropsychiatric illnesses and will have applications for genetic counseling and for differential diagnosis. PUBLIC HEALTH RELEVANCE: The long term objective of this project is to develop validated gene-related tests (genetic biomarkers) to aid in more accurate diagnosis and customized treatment of schizophrenia and related "schizophrenia spectrum" disorders, including bipolar disorder. SureGene's goals for this research are to refine existing genetic biomarkers and to discover and refine additional novel genetic biomarkers. Products based on these biomarkers should be helpful to individuals suffering from schizophrenia and related disorders, their families and health care providers, and researchers seeking to improve diagnosis and treatment.

描述（由申请人提供）：该项目的长期目标是开发经过验证的遗传生物标志物，以帮助更准确的诊断和针对性治疗精神分裂症和相关神经精神疾病，包括双相情感障碍。在第一阶段，Suregene证明了使用精神疾病的特定维度来发现影响风险并影响这些疾病临床表现的新型基因和遗传变异的可行性。该项目将以单核苷酸多态性（SNP）的形式建立在第一代遗传生物标志物上，并以这些多态性的染色体相关性为单倍型。 II期项目将使用一组符合遗传复制标准的基因进一步开发神经精神疾病的生物标志物。该项目将开发用于结合这些基因生物标志物的研究和临床应用的产品。目的是1）为精神分裂症 - 谱系疾病开发原型AssuregenEtm阵列和数据集。 Suregene将开发一种柔性SNP基因分型产品，该产物在大约200个基因中融合了高密度的SNP，并生成了基于2000 NIMH精神分裂症，双极和控制样品的基因型与表型有关的详细数据集。第一代阵列和数据集将在授予年级中期提供给研究社区。在第二阶段结束之前，将完成一个预期临床应用的精制阵列和数据集。 2）评估Assuregenetm检验的效用，以预测临床定义的精神病的发展。 Suregene将开发用于预测二分法临床结果的阵列的遗传算法。该目标应提供一组集体的预测模型，这些模型可以根据其敏感性，特异性和整体分类准确性进行评估。 3）为高优先基因开发和实施一个灵活的医学重新定程平台（ExonReadTM）。 Suregene将开发一个具有成本效益的“下一代”医学重新定位平台，研究界可以使用该平台来评估罕见或自发突变在关键基因中的贡献，这是有助于神经精神疾病的心理病理学和临床结果。研究用途的原型测序平台将在第2年完成。Suregene将对具有精神分裂症或双相情感障碍家族史的非裔美国人和高加索人的样本应用外读，以建立产品的基线期望和局限性。这些产品的商业潜力很重要。通过靶向通用变体，AssuregenEtm阵列应在研究和临床环境中具有广泛的适用性，并具有诊断和药物遗传学应用。 ExonReadTM平台将是一个有价值的，具有成本效益的工具，用于识别在神经精神疾病的家族病例中预期的罕见或独特的高渗透突变，并将针对遗传咨询和进行鉴别诊断。 公共卫生相关性：该项目的长期目标是开发验证的基因相关测试（遗传生物标志物），以帮助更准确的诊断和对精神分裂症和相关“精神分裂症谱系疾病”（包括双相情感障碍）的定制治疗。 Suregene的这项研究目标是完善现有的遗传生物标志物，并发现和完善其他新型的遗传生物标志物。基于这些生物标志物的产品应有助于患有精神分裂症和相关疾病的人，其家庭和医疗保健提供者，以及寻求改善诊断和治疗的研究人员。