成人唐氏综合征中tau神经成像和血浆生物标志物的全基因组关联

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-16 DOI:10.1002/alz.70398

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

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引用次数: 0

摘要

唐氏综合征（DS）血浆生物标志物可准确检测阿尔茨海默病（AD）病理。本研究旨在鉴定与DS患者血浆tau生物标志物（磷酸化tau [p-tau]181， p-tau] 217，总tau [t-tau]）和tau正电子发射断层扫描（PET）相关的遗传位点。方法：我们研究了375名来自阿尔茨海默病生物标志物联盟-唐氏综合征（ABC-DS）的DS患者，包括所有四种tau生物标志物的数据，以及133名来自另一项具有血浆t-tau的DS研究的受试者。进行了单性状和多性状遗传关联分析。用tau生物标志物检测AD多基因风险评分（PRSs）。结果P -tau181基因有3个全基因组显著关联：TUBAP/rs76523946， P = 2.21E-08；CTNND2/rs142510573, P = 3.04E-08；CLSTN2/rs112448655, P = 3.04E-08， t-tau基因1个（JHY/rs77264104, P = 2.84E-08）。AD PRS与tau PET （β = 0.30, P = 6.57E-04）、P -tau217 （β = 0.11, P = 4.10E-02）和t-tau （β = 0.12, P = 3.60E-02）浓度升高相关。这些数据表明，DS中存在影响血浆tau生物标志物的新基因位点，AD风险PRS可能会改变DS的tau神经影像学和血浆生物标志物。4个位点与血浆总tau （t-tau）或磷酸化tau (p-tau)181相关，具有全基因组意义。在一项meta全基因组关联研究（GWAS）中，JHY/rs77264104对血浆t-tau保持全基因组显著性。阿尔茨海默病（AD）多基因风险评分与tau正电子发射断层扫描（PET）相关，与载脂蛋白E基因型和区域无关。唐氏综合征（DS）的tau - pet基因在脑脊液磷酸化tau阿尔茨海默病痴呆GWAS目录中富集。在轻度认知障碍队列的言语记忆GWAS目录中，DS中的T-tau基因富集。

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Genome-wide association of tau neuroimaging and plasma biomarkers in adults with Down syndrome

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Genome-wide association of tau neuroimaging and plasma biomarkers in adults with Down syndrome

INTRODUCTION

Plasma biomarkers in Down syndrome (DS) accurately detect Alzheimer's disease (AD) pathology. This study aimed to identify genetic loci associated with plasma tau biomarkers (phosphorylated tau [p-tau]181, p-tau217, total tau [t-tau]) and tau positron emission tomography (PET) in DS.

METHODS

We examined 375 people with DS from the Alzheimer's Biomarker Consortium–Down Syndrome (ABC-DS) with data on all four tau biomarkers, and 133 subjects from another study of DS with plasma t-tau. Single-trait and multi-trait genetic association analyses were conducted. AD polygenic risk scores (PRSs) were tested with tau biomarkers.

RESULTS

Three genome-wide significant associations were identified for p-tau181: TUBAP/rs76523946, P = 2.21E-08; CTNND2/rs142510573, P = 3.04E-08; CLSTN2/rs112448655, P = 3.04E-08, and one for t-tau (JHY/rs77264104, P = 2.84E-08). AD PRS was associated with higher concentrations of tau PET (β = 0.30, P = 6.57E-04), p-tau217 (β = 0.11, P = 4.10E-02), and t-tau (β = 0.12, P = 3.60E-02).

DISCUSSION

These data indicate the presence of novel genetic loci in DS affecting plasma tau biomarkers and that AD risk PRS may modify tau neuroimaging and plasma biomarkers in DS.

Highlights

Four loci were linked to plasma total tau (t-tau) or phosphorylated tau (p-tau)181 with genome-wide significance.
JHY/rs77264104 stays genome-wide significant for plasma t-tau in a meta genome-wide association study (GWAS).
Alzheimer's disease (AD) polygenic risk score is associated with tau positron emission tomography (PET), regardless of apolipoprotein E genotype and region.
Tau-PET genes in Down syndrome (DS) are enriched in the cerebrospinal fluid phosphorylated tau Alzheimer's disease dementia GWAS catalog.
T-tau genes in DS are enriched in a verbal memory GWAS catalog within a mild cognitive impairment cohort.

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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.