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

描述（由申请人提供）： 阿尔茨海默氏病是已知的有很强的遗传基础，但它不是很好地理解。先前对显性遗传性阿尔茨海默病家族的研究大大提高了我们对β-淀粉样蛋白在疾病中作用的理解。这为更广泛地了解阿尔茨海默病不仅在这些罕见家族的个体中，而且在那些具有常见疾病形式的个体中的发展铺平了道路。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，这是正在进行的。我们的研究旨在通过确定疾病的新遗传机制来寻找其他治疗靶点。我们的目标是在一个具有高度外显性、显性遗传的晚发性阿尔茨海默病大家族中确定阿尔茨海默病的新遗传原因。在过去的11年里，这个家庭被美国国立卫生研究院资助的埃默里阿尔茨海默病研究中心的研究人员招募。我们目前招募了143人，其中112人捐献了生物标本，他们跨越了3个主要分支的原始创始人的10代人。遗传筛查显示没有家族成员具有导致AD的突变。在我们的提案中，我们将尖端技术和经典遗传技术结合起来，在一个多代大家庭中发现导致AD的基因。因为这个家系中的个体是远亲，但继续传播AD作为一种显性遗传性状，我们假设他们共享一个罕见的或以前描述的AD引起的突变。为了验证这一假设，我们建议使用全外显子组测序来鉴定12个远亲受影响成员中所有罕见或先前描述的遗传变异。接下来，我们将测试12个受影响个体之间共享的变异是否与整个谱系中的AD共分离。因为大约有10代人分离受影响的个体，所以在整个谱系中与AD共分离的任何变体都可能是因果关系，因为变体与AD共分离的可能性极低，因为仅凭偶然性就不太可能超过许多代。为了更好地理解含有共分离变体的基因在AD中的作用，我们将检查（1）基因在死后组织中的表达和（2）使用独立群组确定基因对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.