Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
HGG Adv. 2023 Oct 12;4(4):100241. doi: 10.1016/j.xhgg.2023.100241. Epub 2023 Sep 22.
Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.
阿尔茨海默病（AD）是最常见的痴呆症类型，据估计影响了 600 万美国人。AD 的风险是多因素的，包括遗传和环境风险因素。AD 的基因组研究通常侧重于识别风险变异。利用这些信息，可以计算多基因风险评分（PRS）来量化个体由于遗传因素导致的相对疾病风险。阿米什人是一个起源于德国和瑞士再洗礼派移民的创始人群体。他们抵达美国后经历了遗传瓶颈，这使得他们的遗传结构与更广泛的欧洲祖先群体不同。先前的工作表明 PRS 在人群之间的可转移性较差。在这里，我们比较了源自阿米什个体全基因组关联研究（GWAS）的 PRS 与源自大型欧洲祖先 GWAS 的 PRS 的性能。参与者通过进一步评估 AD 进行了认知障碍筛查。在通过 Illumina 基因分型阵列收集后，对基因型数据进行了 imputation。根据主要招募地点，将阿米什个体分为两组。对于每组，进行了 GWAS 分析，考虑了相关性并调整了协变量。然后使用另一个阿米什群体的权重计算 PRS。评估了有无协变量的 PRS 模型。在我们的阿米什人群中，与欧洲衍生的 PRS 相比，源自阿米什人群的 PRS 能更好地区分痴呆状态，并且尽管训练样本量较小，但表现仍有所改善。这项工作强调了在不能仅通过基本种族/民族或祖先分类来充分描述的人群中使用 AD PRS 时需要考虑的因素。
