Willett Julian Daniel Sunday, Mullin Kristina, Tanzi Rudolph E, Prokopenko Dmitry
Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA.
medRxiv. 2025 Jan 19:2025.01.18.25320774. doi: 10.1101/2025.01.18.25320774.
Alzheimer's disease (AD) is the most common form of dementia in elderly, affecting 6.9 million individuals in the United States. Some studies have suggested the prevalence of AD is greater in individuals who self-identify as Hispanic. Focused results are relevant for personalized and equitable clinical interventions. Ethnicity as a stratifying tool in genetic studies is often accompanied by genomic inflation due to heterogeneity. In this study, we report GWAS and meta-analyses conducted among NIAGADS subjects who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components, with and without age and sex. In Hispanic NIAGADS subjects, we identified a common variant in that was protective for AD with a p-value just beyond genome-wide significance (p = 5.4 * 10). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 (), rs192423465 (), and rs935208076 (), which were also nominally significant in AoU sub-cohorts. We also show how genomic inflation can be mitigated in heterogeneous populations while increasing sample size and result generalizability.
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，在美国影响着690万人。一些研究表明，自我认定为西班牙裔的个体中AD的患病率更高。针对性的研究结果对于个性化和公平的临床干预具有重要意义。在基因研究中，将种族作为分层工具时，由于异质性，往往会伴随着基因组膨胀。在本研究中，我们报告了在自我认定为西班牙裔的NIAGADS受试者以及与该队列匹配的“我们所有人”（AoU）子队列中进行的全基因组关联研究（GWAS）和荟萃分析，使用了预测的遗传主成分，同时考虑了年龄和性别因素以及未考虑年龄和性别因素的情况。在西班牙裔NIAGADS受试者中，我们在某基因中发现了一个常见变异，该变异对AD具有保护作用，其p值略高于全基因组显著性水平（p = 5.4 * 10）。与基因匹配的AoU参与者进行的荟萃分析基于罕见的先导变异产生了三个（两个是新发现的）全基因组显著的AD相关位点：rs374043832（某基因）、rs192423465（某基因）和rs935208076（某基因），这些位点在AoU子队列中也具有名义上的显著性。我们还展示了如何在异质人群中减轻基因组膨胀，同时增加样本量并提高结果的普遍性。
