Genetic modifiers of Predict-HD phenotypes

描述（由申请人提供）：亨廷顿氏病（HD）是由CAG扩增突变引起的，其长度是诊断性运动体征出现年龄的主要决定因素，通常在中年。CAG重复序列的长度也与首次出现这些特征的患者出现认知或精神临床症状的年龄相关。因此，CAG重复序列的长度影响了HD早期开始的生物学变化的速率，由于突变的亨廷顿蛋白的表达，导致较晚的运动、认知或精神发病，尽管这三个致病过程的所有步骤可能并不完全相同。然而，出现运动体征的年龄，以及可能出现认知、精神和影像学异常的时间，受到其他尚未确定的遗传因素的影响，这些遗传因素不是独立的风险因素，而是作为修饰因子，即依赖于CAG重复扩增的表型的抑制因子或增强因子。PREDICT-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，已经在各个领域积累了丰富的数据，包括脑成像、运动体征、认知障碍和精神表现，这些数据代表了识别潜在修饰因子的宝贵资源。通过遗传疾病研究中心（CIDR），我们最近为预测-HD生成了全基因组SNP数据，我们还用来自亨廷顿研究小组队列研究、欧洲亨廷顿病网络注册研究和一组储存的死后HD大脑的6000多名HD患者的全基因组SNP数据补充了这些数据。使用PREDICT-HD与这些其他数据集相结合的协调策略，提供了通过增强或抑制其时间和/或修改其表型表达来确定影响由HD突变触发的疾病途径的遗传修饰因子的机会。为了确定改变HD病程的遗传因素，我们将结合全基因组关联（GWA）对HD表型的常见变异进行定量分析，并对“极端”个体的全外显子组测序鉴定出的罕见snp进行分析，这些个体的表型与cag长度和年龄的预期差异很大。我们的目标的完成将推动HD研究朝着有效治疗的方向发展，因为修饰基因的鉴定可以改变人类患者的疾病发病率或表达，可以为治疗开发提供“预先验证”的靶标，以及分层临床试验的新工具，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.