Identifying Alzheimer's disease genes using genomic and family data

描述（由申请人提供）：该K99/R 00独立之路奖的目标是1）教Marchani博士如何在特定的感兴趣基因组区域内识别影响阿尔茨海默病发病年龄的遗传变异，以便她可以，2）开发一个独立的研究计划，优先考虑其他感兴趣的基因组区域，并在其他数据集中发现其他此类遗传变异。Marchani博士的研究生教育使她具备了检测种群结构、测量遗传多样性以及构建和测试解释这种变异的假设的能力。作为一名博士后研究员，她最近发表的证据表明，除了APP，PSEN 1，PSEN 2和APOE之外，还有几个基因影响阿尔茨海默病。她有能力找到可能含有影响阿尔茨海默病风险的变异的基因组区域，但需要额外的培训来确定哪些遗传变异实际上是负责的。在该奖项的指导K99阶段，她和她的导师将1）通过高分辨率映射来完善这些感兴趣的区域，2）通过对缩小的区域进行DNA重测序来识别候选遗传变异。在该奖项的独立R 00阶段，Marchani博士将验证所发现的变异（及其修饰的基因）对阿尔茨海默病发病年龄变化的影响，并撰写和提交新的拨款提案以进一步询问这些基因。 众所周知，阿尔茨海默病（AD）具有很强的遗传基础。APP，PSEN 1和PSEN 2基因的罕见突变导致早发性AD（EOAD），APOE的常见变异有助于早发性AD和晚发性AD（LOAD）的风险和发病年龄（AAO）。除了载脂蛋白E，很难确定LOAD的相关基因。然而，少数基因组区域提供了一致的证据，表明在多个独立的基于谱系的样本中与LOAD存在连锁关系，包括我们在一个独特的队列中确定的三个区域。鉴于目前对复杂性状的理解，这些区域可能含有基因或控制区域，这些基因或控制区域具有对遗传率和发病年龄有相当大影响的罕见或不常见等位基因。该提案的目标是应用新的分析和下一代测序技术来找到这些基因或控制区域中的一些。 华盛顿大学（UW）AD收集包含一组大家庭，一个独特的历史背景和强有力的证据，在多个样本中有强有力的证据表明存在连锁关系的地区AD AAO。也支持这些相同区域的其他可用样本包括NIMH和NIA LOAD样本中的一个队列。我们将使用来自这些集合的样本，再加上基因组重测序，以确定潜在的发病年龄变异。我们将使用UW样本的密集SNP基因型来细化感兴趣的区域。在这些缩小的区域中的至少一个内，我们将使用靶向DNA测序来鉴定候选基因/区域。最后，我们将通过直接基因分型、功能研究和/或其他样本采集中的基因分型受试者来随访最有希望的发现。 鉴定具有修饰AD AAO的变体的新基因将是理解AD生物学的重要一步。对所发现的基因或控制区域所涉及的分子途径的检查可能会导致额外的治疗靶点。此外，这项研究将提供有关AD的遗传结构和识别相关风险变异的方法的重要信息，这将有助于复杂性状研究的设计。 公共卫生相关性：阿尔茨海默病（AD）是美国痴呆症最常见的原因，目前还没有已知的治愈方法或有效的预防方法，并且少数减缓疾病进展的药物疗效有限。这项计划的目标是发现对AD发病年龄有强烈影响的新基因。识别影响AD发病年龄的新基因将有助于了解AD的病因，从而获得更好的诊断方法，并改善治疗和预防措施。

DESCRIPTION (provided by applicant): The goals of this K99/R00 Pathway to Independence award are to 1) teach Dr. Marchani how to identify genetic variants influencing age-at-onset of Alzheimer's disease within a specific genomic region of interest, so that she may, 2) develop an independent research program to prioritize other genomic regions of interest and discover other such genetic variants in other data sets. Dr. Marchani's graduate education established her ability to detect population structure, measure genetic diversity and construct and test hypotheses to explain that variation. As a postdoctoral fellow, she has recently published evidence that several genes in addition to APP, PSEN1, PSEN2, and APOE influence Alzheimer's disease. She has the skills to find genomic regions likely to harbor variants influencing Alzheimer's disease risk, but requires additional training to determine which genetic variants are in fact responsible. During the mentored K99 phase of this award, she and her mentors will 1) refine these regions of interest by high-resolution mapping, and 2) identify candidate genetic variants by DNA resequencing the narrowed regions. During the independent R00 phase of this award, Dr. Marchani will validate the contribution of the discovered variants (and the genes they modify) influence variation in age-at- onset of Alzheimer's disease, and write and submit a new grant proposal to further interrogate those genes. It is well-established that Alzheimer disease (AD) has a strong genetic basis. Rare mutations in the APP, PSEN1 and PSEN2 genes lead to early onset AD (EOAD), and common variation in APOE contributes to risk and age-at-onset (AAO) in both early and late onset AD (LOAD). Other than APOE, it has been difficult to identify relevant genes for LOAD. However, a small number of genomic regions have provided consistent evidence for linkage with LOAD across multiple independent pedigree-based samples, including three regions that we identified in a unique cohort. Given the current understanding of complex traits, it is likely these regions harbor genes or control regions with rare or uncommon alleles that have considerable effects on penetrance and age-at-onset. The goal of this proposal is to apply novel analytic and next generation sequencing technologies to find some of these genes or control regions. The University of Washington (UW) AD collection contains a cohort of large families a unique historical background and strong evidence for AD AAO in regions with strong evidence of linkage in multiple samples. Additional available samples that also support these same regions include a cohort within the NIMH and NIA LOAD samples. We will use samples from these collections, coupled with genomic resequencing, to identify the underlying age-at-onset variants. We will use dense SNP genotypes for UW samples to refine the regions of interest. Within at least one of these narrowed regions, we will use targeted DNA sequencing to identify candidate genes/regions. Finally, we will follow-up the most promising findings with direct genotyping, functional studies, and/or genotyping subjects in other sample collections. The identification of novel genes with variants modifying AD AAO would be a significant step towards understanding AD biology. Examination of molecular pathways implicated by the genes or control regions found will likely lead to additional therapeutic targets. In addition, this study will provide important information about the genetic architecture of AD and approaches to identifying the associated risk variants, which will be useful for design of complex-trait studies. PUBLIC HEALTH RELEVANCE: There is no known cure or effective prevention for Alzheimer's disease (AD), the most common cause of dementia in the US, and the few medications that slow the progression of disease have limited efficacy. The goal of this proposal is to discover novel genes that have a strong influence on age-at-onset of AD. Identification of new genes affecting AD age-at-onset will facilitate an understanding of the etiology of AD, lead to better diagnostic methods, and improved therapeutic and preventative measures.