Genetics of Gene Expression and Gene Mapping for Amytrophic Lateral Sclerosis

描述(由申请人提供)：这是一项在肌萎缩侧索硬化症(ALS)患者和匹配对照的样本中进行全基因组基因表达谱分析的建议，这些样本都来自荷兰相对同质的人群。一旦肌萎缩侧索硬化症特异的表达谱被识别，这些表型将被用来识别潜在的遗传变异。复制样本来自相同的人群以及具有ALS相关表型的样本。ALS特异性表达谱的识别等同于发现该病的功能性生物标志物。由于基因表达的变异在很大程度上与遗传变异有关，这些功能生物标记物可以用来识别与ALS复杂的神经功能障碍相关的常见遗传变异。研究群体是遗传学研究的理想群体，因为它的确定、基于群体的样本收集和均匀的群体结构是一致的。这些患者仍然在招募他们参加研究的同一临床医生的照顾下，允许在疾病的时间跨度内进行纵向评估以及基于家庭的后续研究的不同寻常的机会。将使用包含23,000个RefSeq转录本的高通量BeadChip阵列为样本建立全基因组表达谱。为了确定与ALS表型相关的基因表达谱，将应用系统的统计分析。将进行基于网络的分析，以确定表达模块，以及与疾病表型相关的最显著变化(S)。由于这些样本中的绝大多数可通过独立的努力进行高密度300K SNP基因分型，因此表达谱可用作全基因组关联研究的数量性状。后续研究将启动，以进一步描绘与肌萎缩侧索硬化症表达谱相关的潜在遗传变异，以及研究特定的肌萎缩侧索硬化症特征和表达谱。最终，肌萎缩侧索硬化症的功能性生物标志物的开发可以用于诊断目的，并识别与肌萎缩侧索硬化症特异性表达谱和疾病易感性相关的潜在遗传变异。这是一项在肌萎缩侧索硬化症(ALS)患者和匹配对照组的样本中进行全基因组基因表达谱分析的建议，这些患者和对照组都来自荷兰相对同质的人群。

DESCRIPTION (provided by applicant): This is a proposal to perform a genome-wide gene expression profiling in peripheral blood in a sample of Amyotrophic Lateral Sclerosis (ALS) patients and matched controls, all from a relatively homogeneous population in The Netherlands. Once ALS-specific expression profiles have been identified, these will be used as phenotypes to identify underlying genetic variation. A replication sample is available from the same population as well as samples with ALS-related phenotypes. Identification of ALS-specific expression profiles equals the discovery of functional biomarkers for the disease. Since variation in gene expression is to a large degree associated with genetic variation, these functional biomarkers can be used to identify common genetic variants associated with the complex neurological disorder of ALS. The study population is ideal for genetic studies given the uniformity of its ascertainment, the population-based sample collection, and the homogeneous population structure. The patients remain under care of the same clinicians who enrolled them in the study, permitting unusual opportunities for longitudinal evaluations within the time span of the disease, as well as family-based follow-up studies. Genome-wide expression profiles will be established for the sample using the high- throughput BeadChip arrays containing >23,000 RefSeq transcripts. Systematic statistical analyses will be applied in order to identify gene-expression profiles associated with ALS phenotype. Network-based analysis will be performed to identify expression modules, and the most significant changes related to disease phenotype(s). Since for the vast majority of these samples high-density 300K SNP genotyping is available through an independent effort, the expression profiles can be used as quantitative traits for genome-wide association studies. Follow-up studies will be initiated to further delineate the underlying genetic variation associated with ALS expression profiles as well as study of specific ALS characteristics and expression profiles. Ultimately, the developments of functional biomarkers for ALS can be used for diagnostic purposes and identification of underlying genetic variation associated with ALS-specific expression profiles and disease susceptibility. This is a proposal to perform a genome-wide gene expression profiling in peripheral blood in a sample of Amyotrophic Lateral Sclerosis (ALS) patients and matched controls, all from a relatively homogeneous population in The Netherlands.