Genetic modifiers of Predict-HD phenotypes

描述(申请人提供)：亨廷顿病(HD)是由CAG扩增突变引起的，其长度是诊断运动迹象出现的年龄的主要决定因素，通常在中年。CAG重复的长度也与首次出现这些特征的患者的认知或精神临床体征的发病年龄相关。因此，CAG重复长度影响由于突变Huntingtin的表达而在HD中早期开始的生物学变化的速度，导致运动、认知或精神疾病的发病时间较晚，尽管这三个致病过程中的每一个步骤可能并不都相同。然而，运动体征开始时的年龄，以及认知、精神和成像异常的发生时间，都受到其他尚未确定的遗传因素的影响，这些因素不是作为独立的危险因素，而是作为修饰物，即依赖于扩增的CAG重复的存在而抑制或增强表型。Forecast-HD是一项观察性研究，旨在调查HD突变在诊断前几十年的影响，已经在包括脑成像、运动体征、认知障碍和精神表现在内的各个领域积累了丰富的数据，这些数据为识别潜在的修饰因素提供了宝贵的资源。通过遗传病研究中心(CIDR)，我们最近为Forecate-HD生成了全基因组的SNP数据，并用来自Huntington Study Group队列研究、欧洲亨廷顿疾病网络的注册研究和一组储存的HD大脑的全基因组SNP数据补充了这些数据。结合使用Forect-HD和这些其他数据集的协调策略提供了通过增强或抑制HD突变的时机和/或修改其表型表达来识别影响HD突变触发的疾病途径(S)的遗传修饰物的机会。为了确定改变HD进程的遗传因素，我们将结合使用对常见变异的基因组关联(GWA)分析来定量HD表型，以及通过对表型与CAG长度和年龄预期有很大差异的“极端”个体的完整外显子测序识别的罕见SNP的分析。我们的目标的完成将推动HD研究朝着有效的治疗方法发展，因为识别改变人类患者疾病速率或表达的修饰基因可以为治疗开发提供“预先验证的”目标，以及为临床试验分层提供新的工具，以最大限度地提高其信息量。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is caused by a CAG expansion mutation whose length is the primary determinant of the age at which diagnostic motor signs emerge, typically in mid-life. The length of the CAG repeat is also correlated with age of onset of cognitive or psychiatric clinical signs in those who present first with these features. Thus, CAG repeat length influences the rate with which biological changes in HD that begin early, due to the expression of mutant huntingtin, lead much later to motor, cognitive or psychiatric onset, although not all steps in each of these three pathogenic processes are likely to be identical. However, the age at onset of motor signs, and likely the timing of cognitive, psychiatric and imaging abnormalities, is influenced by other as yet unidentified genetic factors, not as independent risk factors but as modifiers, i.e., suppressors or enhancers of phenotypes dependent on the presence of an expanded CAG repeat. PREDICT-HD, which was established as an observational study to investigate the effects of the HD mutation during the decades prior to diagnosis, has accumulated a wealth of data in various domains, including brain imaging, motor signs, cognitive disturbance and psychiatric manifestations, that represent a valuable resource for identifying potential modifiers. Via the Center for Inherited Disease Research (CIDR), we have recently generated genome-wide SNP data for PREDICT-HD, and we have complemented these data with genome-wide SNP data for more than 6,000 HD individuals from the Huntington Study Group COHORT study, the European Huntington Disease Network's Registry study and a collection of banked post-mortem HD brains. A coordinated strategy using PREDICT-HD in combination with these other datasets offers the opportunity to identify genetic modifiers that influence the disease pathway(s) triggered by the HD mutation by enhancing or suppressing its timing and/or modifying its phenotypic expression. To identify genetic factors that alter the course of HD, we will use a combination of genome-wide association (GWA) analysis of common variants to quantitative HD phenotypes and analysis of rare SNPS identified by whole exome sequencing of 'extreme' individuals whose phenotypes differ substantially from those expected from their CAG-length and age. Completion of our aims will advance HD research toward effective therapeutics, as the identification of modifier genes, which alter the rate or expression of the disease in human patients, could provide 'pre-validated' targets for therapeutic development as well as a new tool for stratifying clinical trials to maximie their informativeness.