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）患者和匹配对照样本的外周血中进行全基因组基因表达谱分析的建议，所有患者和对照均来自荷兰相对同质的人群。一旦鉴定出ALS特异性表达谱，这些将被用作表型以鉴定潜在的遗传变异。可从相同人群以及具有ALS相关表型的样本中获得复制样本。ALS特异性表达谱的鉴定等同于发现该疾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相关，因此这些功能性生物标志物可用于鉴定与ALS复杂神经系统疾病相关的常见遗传变异。研究群体是遗传研究的理想选择，因为其确定的一致性，基于群体的样本收集和同质的群体结构。这些患者仍由参加研究的同一位临床医生进行治疗，这使得在疾病发生的时间范围内有不寻常的机会进行纵向评估，以及基于家庭的随访研究。将使用含有> 23，000个RefSeq转录物的高通量BeadChip阵列建立样品的全基因组表达谱。将应用系统的统计分析，以确定与ALS表型相关的基因表达谱。将进行基于网络的分析以鉴定表达模块以及与疾病表型相关的最显著变化。由于这些样本中的绝大多数都可以通过独立的努力进行高密度300K SNP基因分型，因此表达谱可以用作全基因组关联研究的定量性状。后续的研究将开始，以进一步描绘与ALS表达谱相关的潜在遗传变异，以及特定ALS特征和表达谱的研究。最终，ALS功能性生物标志物的发展可用于诊断目的，并鉴定与ALS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）患者和匹配对照样本中进行外周血全基因组基因表达谱分析的建议，所有患者均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.