Eissman Jaclyn M, Qiao Min, Kalia Vrinda, Zerlin-Esteves Marielba, Reyes-Dumeyer Dolly, Piriz Angel, Dubey Saurabh, Nandakumar Renu, Lee Annie J, Lantigua Rafael A, Medrano Martin, Mejia Diones Rivera, Honig Lawrence S, Dalgard Clifton L, Miller Gary W, Mayeux Richard, Vardarajan Badri N
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
Gertrude H. Sergievsky Center, Columbia University, New York, NY, 10032, USA.
medRxiv. 2025 Mar 17:2025.02.26.25322932. doi: 10.1101/2025.02.26.25322932.
We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD). We computed metabolite quantitative trait loci by using whole genome sequencing and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6,881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. We identified 72 novel and known SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including and N6-methyllysine, and myristoylglycine, as well as and arachidonic acid. In addition, we found differences in genetic regulation of metabolites among individuals with clinically defined AD compared to AD defined by a published plasma P-tau181 level cut-off. We also found more SNP-metabolite associations among males compared to females. In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites and unique biological mechanisms of genetic perturbations in AD.
我们研究了循环血浆代谢物的基因调控因子，以确定阿尔茨海默病（AD）临床及生物标志物辅助诊断中生化变化的潜在通路。我们利用全基因组测序以及来自229名患有临床AD的老年人和322名年龄匹配的健康对照的小分子血浆代谢物，计算了代谢物数量性状位点。测试了6881种代谢物与332772个常见基因变异之间的无偏关联，并对年龄、性别以及代谢组学和基因组主成分进行了校正。我们鉴定出72个新的和已知的单核苷酸多态性-代谢物关联，涉及66个基因和12个代谢物类别，包括N6-甲基赖氨酸、肉豆蔻酰甘氨酸以及花生四烯酸。此外，我们发现与根据已发表的血浆P-tau181水平临界值定义的AD相比，临床定义的AD个体之间代谢物的基因调控存在差异。我们还发现男性中的单核苷酸多态性-代谢物关联比女性更多。总之，我们确定了血浆代谢物的性别和疾病特异性基因调控因子以及AD中基因扰动的独特生物学机制。
