BACKGROUND Alzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus. In 2013, the International Genomics of Alzheimer's Project (IGAP) did a meta-analysis of all existing GWAS using data from 74 046 individuals, which stood as the largest Alzheimer's disease GWAS until 2018. This meta-analysis discovered 19 susceptibility loci for Alzheimer's disease in populations of European ancestry. RECENT DEVELOPMENTS Three new Alzheimer's disease GWAS published in 2018 and 2019, which used larger sample sizes and proxy phenotypes from biobanks, have substantially increased the number of known susceptibility loci in Alzheimer's disease to 40. The first, an updated GWAS from IGAP, included 94 437 individuals and discovered 24 susceptibility loci. Although IGAP sought to increase sample size by recruiting additional clinical cases and controls, the two other studies used parental family history of Alzheimer's disease to define proxy cases and controls in the UK Biobank for a genome-wide association by proxy, which was meta-analysed with data from GWAS of clinical Alzheimer's disease to attain sample sizes of 388 324 and 534 403 individuals. These two studies identified 27 and 29 susceptibility loci, respectively. However, the three studies were not independent because of the large overlap in their participants, and interpretation can be challenging because different variants and genes were highlighted by each study, even in the same locus. Furthermore, neither the variant with the strongest Alzheimer's disease association nor the nearest gene are necessarily causal. This situation presents difficulties for experimental studies, drug development, and other future research. WHERE NEXT?: The ultimate goal of understanding the genetic architecture of Alzheimer's disease is to characterise novel biological pathways that underly Alzheimer's disease pathogenesis and to identify novel drug targets. GWAS have successfully contributed to the characterisation of the genetic architecture of Alzheimer's disease, with the identification of 40 susceptibility loci; however, this does not equate to the discovery of 40 Alzheimer's disease genes. To identify Alzheimer's disease genes, these loci need to be mapped to variants and genes through functional genomics studies that combine annotation of variants, gene expression, and gene-based or pathway-based analyses. Such studies are ongoing and have validated several genes at Alzheimer's disease loci, but greater sample sizes and cell-type specific data are needed to map all GWAS loci.

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阿尔茨海默病全基因组关联研究中风险位点的解读

背景技术阿尔茨海默病是一种使人衰弱且高度遗传的神经系统疾病。因此，自 20 世纪 90 年代以来，遗传学研究一直致力于了解阿尔茨海默病的遗传结构，并相继开展了更大规模的全基因组关联研究 (GWAS) 和荟萃分析。这些研究始于 2007 年的 1086 人小样本，仅能鉴定出 APOE 基因座。2013年，国际阿尔茨海默病基因组学项目（IGAP）利用74046名个体的数据对所有现有的GWAS进行了荟萃分析，这是截至2018年最大的阿尔茨海默病GWAS。这项荟萃分析发现了19个阿尔茨海默病的易感位点在欧洲血统的人群中。最新进展 2018 年和 2019 年发布的三项新的阿尔茨海默病 GWAS 使用了更大的样本量和来自生物库的代理表型，将阿尔茨海默病已知易感位点的数量大幅增加到 40 个。第一个是 IGAP 更新的 GWAS，其中包括 94 个437人，发现24个易感位点。尽管 IGAP 试图通过招募额外的临床病例和对照来增加样本量，但另外两项研究使用阿尔茨海默氏病的父母家族史来定义英国生物银行中的代理病例和对照，以通过代理进行全基因组关联，并进行荟萃分析利用临床阿尔茨海默病 GWAS 的数据，获得了 388 324 人和 534 403 人的样本量。这两项研究分别鉴定了 27 个和 29 个易感位点。然而，这三项研究并不是独立的，因为它们的参与者有很大的重叠，并且解释可能具有挑战性，因为每项研究都强调了不同的变异和基因，即使是在同一位点。此外，与阿尔茨海默病关联最强的变异和最接近的基因都不一定是因果关系。这种情况给实验研究、药物开发和其他未来的研究带来了困难。下一步在哪里？：了解阿尔茨海默病遗传结构的最终目标是表征阿尔茨海默病发病机制的新生物途径，并确定新的药物靶点。GWAS 已成功地对阿尔茨海默病遗传结构的表征做出了贡献，鉴定了 40 个易感位点；然而，这并不等于发现了40个阿尔茨海默病基因。为了识别阿尔茨海默病基因，需要通过功能基因组学研究将这些基因座映射到变异和基因，该研究结合了变异注释、基因表达以及基于基因或基于通路的分析。此类研究正在进行中，并验证了阿尔茨海默病基因座的多个基因，但需要更大的样本量和细胞类型特定数据来绘制所有 GWAS 基因座。