Further defining the genetic architecture of Alzheimer's disease

阿尔茨海默病是一种常见的衰弱障碍，影响个人、家庭和社区。英国有不到50万人患有阿尔茨海默病(AD)，估计每年的成本为230亿GB。据估计，在下一代，患有AD的人数将翻一番。至关重要的是，我们必须了解这种疾病的原因，并开发预防、延迟和治疗它的疗法。找到影响阿尔茨海默病发育的基因是准确定位出错并导致脑细胞死亡的过程的重要手段，这是这种疾病的特征，也是记忆丧失和普遍认知退化的症状的基础。在过去的25年里，大约四分之一的疾病基因贡献者已经被确定，我们的团队在这方面发挥了关键作用，最近发现了AD常见的10个风险变异中的8个。这让我们重新思考了我们对导致疾病的具体过程的一些看法。这些基因聚集在一起形成群体，与我们的免疫反应、我们如何在大脑中处理胆固醇等脂质以及一种名为内吞作用的特定过程有关，内吞作用将大分子带入细胞，并影响它们在细胞内的运输，如神经元。但超过一半的基因对疾病的贡献尚未被发现。我们提出了一项建立在我们目前优势基础上的研究计划，重点是识别在基因编码区观察到的中等到强烈影响的罕见遗传变异。我们将进行一项大规模、强有力的研究，比较来自整个人类基因组的300,000个DNA变异，其中包括20,000个AD病例和49,000个对照。通过样本收集和合作，我们将丰富我们的临床样本，包括1000名早发性阿尔茨海默病患者。这一群体更有可能有罕见的基因变化，对他们的疾病发展有中等到很大的影响。这项实验有很好的机会识别AD的新风险基因，产生更适合在人类细胞中建立疾病模型的靶点，并产生新的治疗方法。我们还将通过使用最新的干细胞技术(可诱导多能干细胞：IPSC)生产适合人类疾病建模的细胞系生物库，并将其提供给研究界和制药公司，从而促进未来的研究。

Alzheimer's disease is a common debilitating disorder which affects individuals, families and communities. Just under half a million people have Alzheimer's disease (AD) in the UK with an estimated cost of £23 billion per year. It is also estimated that the numbers with AD will double in the next generation. It is vital we understand what causes this disease and develop therapies to prevent, delay and treat it. Finding genes which affect the development of AD is an important means to pinpoint processes that are going wrong and contributing to the death of brain cells, which characterises this disease and underlies the symptoms of memory loss and general cognitive degeneration. Over the last 25 years approximately a quarter of the genetic contributors to disease have been identified and our group have played a pivotal role in this and have recently discovered 8 of the 10 common risk variants for AD. This has made us re-think some of our ideas about the specific processes which contribute to disease. These genes cluster together to form groups, implicating processes like our immune response, how we process lipids like cholesterol in the brain and a specific process called endocytosis, which brings large molecules into cells and affects their transport within cells, such as neurons. But over half the genetic contribution to disease is yet to be found. We propose a programme of research which builds on our current strengths, focusing on identifying rare genetic variants of moderate to strong effect observed in the coding regions of genes. We will perform a large, powerful study in which we compare 300,000 DNA variants from throughout the human genome, in 20,000 AD cases and 49,000 controls. Through sample collection and collaboration, we will enrich our clinical samples to include 1000 individuals with early onset AD. This group are more likely to have rare genetic changes of moderate to large effect on their development of disease. This experiment has an excellent chance of identifying new risk genes for AD and producing targets better suited to model disease in human cells and produce new therapeutics. We will also facilitate future research by producing a bio-bank of cell lines suitable for human modelling of disease using the latest stem cell technology (inducible pluripotent stem cells: iPSC) and making this available to the research community and pharmaceutical companies.