Genome-wide association analyses identify candidate loci for amyloid imaging and plasma biomarkers in adults with Down syndrome

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-16 DOI:10.1002/alz.70358

M. Muaaz Aslam, Lam-Ha T. Dang, Ruyu Shi, Kang-Hsien Fan, Asma Naseer Cheema, Laura Xicota, Danveet Minhas, Weiquan Luo, Narges Zafari, Vibha Acharya, Eleanor Feingold, Sharon Krinsky-McHale, Charles M. Laymon, Ann Cohen, Benjamin L. Handen, Bradley T. Christian, Elizabeth Head, Mark E. Mapstone, Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS), Joseph H. Lee, Carlos Cruchaga, M. Ilyas Kamboh

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引用次数: 0

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

DISCUSSION

Despite the small sample, our findings highlight the unique genetic architecture of amyloid burden in DS.

Highlights

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.

Abstract Image

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全基因组关联分析确定成人唐氏综合征淀粉样蛋白成像和血浆生物标志物的候选位点

唐氏综合征（DS）患者由于21号染色体上淀粉样蛋白前体蛋白（APP）基因的三倍复制而过量产生β淀粉样蛋白（Aβ），从而在年轻时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，以了解DS中淀粉样蛋白负荷的遗传结构。方法对阿尔茨海默病生物标志物联盟-唐氏综合征（ABC-DS）参与者的淀粉样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，然后对血浆Aβ生物标志物数据进行荟萃分析。结果血浆生物标志物荟萃分析鉴定出4个新的基因座：2个用于Aβ42 (PFKFB3/rs147647642, p = 2.83E-08；DLX3-PICART1/rs12952028, p = 9.31E-09)和2个a - β40 (LINC01941-GYPC/rs78338676, p = 9.33E-09；PDE4D/rs146261781, p = 9.97E-08)。在ABC-DS队列中观察到淀粉样蛋白pet的5个全基因组信号，需要在独立的DS数据集中确认。尽管样本量小，但我们的发现强调了DS中淀粉样蛋白负荷的独特遗传结构。发现了唐氏综合征（DS）淀粉样蛋白生物标志物的遗传标记。荟萃分析在两个DS队列中发现了四个新的血浆淀粉样蛋白位点。在阿尔茨海默病生物标志物联盟-唐氏综合征队列中发现了5个与淀粉样蛋白正电子发射断层扫描水平相关的基因座。多性状分析揭示了与淀粉样蛋白生物标志物相关的基因座。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.