The Familial Alzheimer Sequencing (FASe) Project

摘要 基于家庭的方法导致了导致阿尔茨海默病(AD)的变种在 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，对这些基因的识别导致了Aβ-Casade假说，最近又导致了 开发针对这一途径的药物。在这项建议中，我们将识别罕见的风险和保护性等位基因。 在最近的一项研究中，我们发现了TREM2中一种罕见的编码变体，对AD的风险具有较大的影响大小，证实了 罕见的编码变异在阿尔茨海默病的病因中发挥了作用。我们将密集使用来自家庭的序列数据 受阿尔茨海默病的影响，因为我们假设这些家庭具有丰富的遗传风险因素。我们已经 可以获得来自695个家庭(2462个人)的序列数据，这些数据与ADSP数据相结合将 形成了一个非常大的基于家庭的数据集：超过805个家庭和4512名参与者。我们的预赛 结果支持这种方法的灵活性，并强烈表明保护性和风险变量具有较大的 效果大小将会被找到。对这些变异和基因的鉴定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.