Aslam M Muaaz, Dang Lam-Ha T, Shi Ruyu, Fan Kang-Hsien, Cheema Asma Naseer, Xicota Laura, Minhas Danveet, Luo Weiquan, Zafari Narges, Acharya Vibha, Feingold Eleanor, Krinsky-McHale Sharon, Laymon Charles M, Cohen Ann, Handen Benjamin L, Christian Bradley T, Head Elizabeth, Mapstone Mark E, Lee Joseph H, Cruchaga Carlos, Kamboh M Ilyas
Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.
Sergievsky Center, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Alzheimers Dement. 2025 Jul;21(7):e70358. doi: 10.1002/alz.70358.
People with Down syndrome (DS) overproduce amyloid-beta (Aβ) due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and consequently accumulate brain amyloid load at younger ages. We conducted genome-wide association (GWA) analyses on amyloid imaging and plasma biomarkers to discern the genetic architecture of amyloid burden in DS.
GWA analyses were performed on amyloid positron emission tomography (PET) and plasma biomarkers (Aβ40, Aβ42, Aβ42/40 ratio) in participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) and on plasma Aβ biomarkers available in an independent DS cohort, followed by meta-analysis of plasma Aβ biomarker data.
Meta-analysis on plasma biomarkers identified four novel loci: two for Aβ42 (PFKFB3/rs147647642, p = 2.83E-08; DLX3-PICART1/rs12952028, p = 9.31E-09) and two for Aβ40 (LINC01941-GYPC/rs78338676, p = 9.33E-09; PDE4D/rs146261781, p = 9.97E-08). Five genome-wide signals were observed for amyloid-PET in the ABC-DS cohort that need confirmation in an independent DS dataset.
Despite the small sample, our findings highlight the unique genetic architecture of amyloid burden in DS.
Genetic markers for amyloid biomarkers in Down syndrome (DS) were identified. Meta-analyses identified four novel loci for plasma amyloid in two DS cohorts. Five loci associated with amyloid positron emission tomography levels were identified in the Alzheimer's Biomarker Consortium-Down Syndrome cohort. Multi-trait analysis revealed loci linking variants to amyloid biomarkers.
由于21号染色体上淀粉样前体蛋白（APP）基因的三倍体，唐氏综合征（DS）患者会过度产生β淀粉样蛋白（Aβ），因此在较年轻时就会积累脑淀粉样蛋白负荷。我们对淀粉样蛋白成像和血浆生物标志物进行了全基因组关联（GWA）分析，以识别DS中淀粉样蛋白负荷的遗传结构。
对来自阿尔茨海默病生物标志物联盟唐氏综合征（ABC-DS）的参与者的淀粉样蛋白正电子发射断层扫描（PET）和血浆生物标志物（Aβ40、Aβ42、Aβ42/40比值）以及独立DS队列中可用的血浆Aβ生物标志物进行GWA分析，随后对血浆Aβ生物标志物数据进行荟萃分析。
血浆生物标志物的荟萃分析确定了四个新位点：两个与Aβ42相关（PFKFB3/rs147647642，p = 2.83E-08；DLX3-PICART1/rs12952028，p = 9.31E-09），两个与Aβ40相关（LINC01941-GYPC/rs78338676，p = 9.33E-09；PDE4D/rs146261781，p = 9.97E-08）。在ABC-DS队列中，淀粉样蛋白PET观察到五个全基因组信号，需要在独立的DS数据集中进行确认。
尽管样本量较小，但我们的研究结果突出了DS中淀粉样蛋白负荷独特的遗传结构。
确定了唐氏综合征（DS）中淀粉样蛋白生物标志物的遗传标记。荟萃分析在两个DS队列中确定了四个血浆淀粉样蛋白的新位点。在阿尔茨海默病生物标志物联盟唐氏综合征队列中确定了五个与淀粉样蛋白正电子发射断层扫描水平相关的位点。多性状分析揭示了将变体与淀粉样蛋白生物标志物联系起来的位点。
