The Familial Alzheimer Sequencing (FASe) Project

摘要 以家族为基础的方法导致在阿尔茨海默氏病（AD）中识别出致病的阿尔茨海默氏病（AD）变体。 编码淀粉样β前体蛋白（APP）、早老素1（PSEN1）和早老素2（PSEN2）的基因。 随后，这些基因的鉴定导致了Aβ级联假说，最近又导致了Aβ级联假说。 开发针对该途径的药物。在这项提案中，我们将确定罕见的风险和保护等位基因。 在最近的一项研究中，我们在TREM2中发现了一种罕见的编码变体，其对AD风险的效应量很大，证实了 罕见的编码变异在AD的病因学中起作用。我们将密集使用来自家族的序列数据 因为我们假设这些家庭富含遗传风险因素。我们已经 可以访问来自695个家庭（2，462个个体）的序列数据，与ADSP数据相结合， 这导致了一个非常大的基于家庭的数据集：超过805个家庭和4，512名参与者。我们的初步 结果支持这种方法的灵活性，并强烈表明，保护性和风险变异与大 这些变异和基因的识别将有助于更好地理解 疾病的生物学。

Abstract Family-based approaches led to the identification of disease-causing Alzheimer’s Disease (AD) variants in the genes encoding amyloid-beta precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Subsequently, the identification of these genes led to the Aβ-cascade hypothesis and recently to the development of drugs that target that pathway. In this proposal, we will identify rare risk and protective alleles. In a recent study, we identified a rare coding variant in TREM2 with large effect size for risk for AD, confirming that rare coding variants play a role in the etiology of AD. We will use sequence data from families densely affected by AD, because we hypothesize that these families are enriched for genetic risk factors. We already have access to sequence data from 695 families (2,462 individuals), that combined with the ADSP data will lead to a very large family-based dataset: more than 805 families and 4,512 participants. Our preliminary results support the flexibility of this approach and strongly suggest that protective and risk variants with large effect size will be found. The identification of those variants and genes will lead to a better understanding of the biology of the disease.