A Genetic Study of a Large Pedigree with Late-onset Alzheimer's Disease

描述(由申请人提供)： 众所周知，阿尔茨海默氏症有很强的遗传基础，但人们对它的了解还不够清楚。先前对以遗传为主的阿尔茨海默病家族的研究极大地促进了我们对β-淀粉样蛋白在疾病中的作用的理解。这为更广泛地了解阿尔茨海默病是如何发展的铺平了道路，不仅在这些罕见家庭的个体中，而且在那些患有常见疾病的人中。最终，这些见解指导了新疗法的开发，以阻止或减缓这种毁灭性和无情的疾病的进展，这种疾病正在进行中。我们的研究试图通过识别疾病的新遗传机制来寻找更多的治疗靶点。我们的目标是在一个高渗透性、以遗传为主的晚发性阿尔茨海默病大家庭中确定阿尔茨海默病的新遗传原因。在过去的11年里，这个家庭一直被NIA资助的埃默里阿尔茨海默病研究中心的研究人员招募。我们目前已经招募了143人，其中112人捐赠了生物标本，他们跨越了最初创始人在3个主要分支机构的10代人。基因筛查显示，没有家庭成员携带导致AD的突变。在我们的建议中，我们将尖端技术和经典基因技术结合起来，在一个多代人的大家庭中发现导致AD的基因。由于这个家系中的个体是远亲，但继续将AD作为一种显性遗传特征传播，我们假设他们共享一种罕见的或先前描述的导致AD的突变。为了验证这一假设，我们建议使用全外显子组测序在该家族的12个远亲成员中识别所有罕见的或先前描述的遗传变异。接下来，我们将测试在12个受影响的个体之间共享的变异是否与整个家系中的AD共同分离。因为大约有10个世代分离受影响的个体，所以在整个家系中与AD共分离的任何变异都可能是原因，因为一个变异不太可能单独与AD OVE共分离那么多世代。为了更好地了解包含共分离变体的基因在AD中的作用，我们将检测(1)该基因在死后组织中的表达，以及(2)使用一个独立的队列来确定该基因对AD的遗传贡献。

DESCRIPTION (provided by applicant): Alzheimer's disease is known to have a strong genetic basis, but it is not well understood. Prior work on families with dominantly inherited Alzheimer's disease significantly advanced our understanding of the role of beta-amyloid in the disease. This paved the way to a broader understanding of how Alzheimer's disease develops not only in individuals from these rare families but in those with common forms of the disease. Ultimately, these insights have guided the development of new therapies to halt or slow the progression of this devastating and relentless disease, which are ongoing. Our study seeks to find additional therapeutic targets by identifying new genetic mechanisms of disease. We aim to identify new genetic causes of Alzheimer's disease in a large family with highly penetrant, dominantly inherited late-onset Alzheimer's disease. This family has been recruited over the last 11 years by researchers at the NIA-funded Emory Alzheimer's Disease Research Center. We currently have recruited 143 individuals, including 112 who have donated biological specimens, who span 10 generations from the original founders in 3 major branches. Genetic screening revealed no family member with an AD-causing mutation. In our proposal, we marry cutting-edge technology and classical genetic techniques to discover the AD-causing gene in a large multi-generational family. Because individuals in this pedigree are distantly related but continue to transmit AD as a dominantly inherited trait, we hypothesize that they share a rare or previously described AD-causing mutation. To test this hypothesis, we propose to identify all rare or previously described genetic variants among 12 distantly related affected members of this kindred using whole-exome sequencing. Next, we will test whether variants that are shared among the 12 affected individuals co-segregate with AD in the entire pedigree. Because there are approximately 10 generations separating affected individuals any variant that co-segregates with AD in the entire pedigree is likely causal since it is highly unlikely that a variant would co-segregate with AD ove that many generations by chance alone. To better understand the role of the gene containing the co-segregating variant in AD, we will examine the (1) expression of the gene in post- mortem tissue and (2) determine the genetic contribution of the gene to AD using an independent cohort.