Genetic modifiers of Predict-HD phenotypes

描述（由申请人提供）：亨廷顿病（HD）由CAG扩增突变引起，其长度是诊断性运动体征出现的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认知或精神临床体征的患者的发病年龄相关。因此，CAG重复序列长度影响HD中的生物学变化的速率，所述生物学变化由于突变亨廷顿蛋白的表达而开始较早，导致运动、认知或精神病发作较晚，尽管这三个致病过程中的每一个中的所有步骤都可能是相同的。然而，运动体征发作时的年龄，以及认知、精神和影像学异常的可能时间，受到其他尚未确定的遗传因素的影响，这些因素不是独立的风险因素，而是修饰因素，即，依赖于扩增的CAG重复序列的存在的表型的抑制子或增强子。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，在各个领域积累了丰富的数据，包括脑成像，运动体征，认知障碍和精神病学表现，这是识别潜在修饰剂的宝贵资源。通过遗传性疾病研究中心（CIDR），我们最近生成了PREDICT-HD的全基因组SNP数据，并将这些数据与来自亨廷顿研究组COHORT研究、欧洲亨廷顿疾病网络登记研究和一组储存的死后HD大脑的6,000多名HD个体的全基因组SNP数据进行了补充。使用PREDICT-HD与这些其他数据集组合的协调策略提供了鉴定遗传修饰剂的机会，所述遗传修饰剂通过增强或抑制其时机和/或修饰其表型表达来影响由HD突变触发的疾病途径。为了确定改变HD病程的遗传因素，我们将使用全基因组关联（GWA）分析常见变异的定量HD表型和分析罕见SNPS的组合，通过全外显子组测序确定的“极端”个体的表型与其CAG长度和年龄的预期有很大不同。我们的目标的完成将推进HD研究向有效的治疗方法，作为修饰基因的鉴定，改变人类患者的疾病的速率或表达，可以提供“预先验证”的治疗发展目标，以及一个新的工具，分层临床试验，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.