Thomas W. Marsh, Daniel Western, Jigyasha Timsina, Priyanka Gorijala, Chengran Yang, Pau Pastor, Menghan Liu, John C. Morris, Randall J. Bateman, Suzanne E. Schindler, Yun Ju Sung, Dominantly Inherited Alzheimer Network, Carlos Cruchaga
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引用次数: 0
摘要
导言：有人建议用血浆替代脑脊液（CSF）来测量阿尔茨海默病（AD）的生物标志物，但还没有研究详细分析哪种生物流体对AD遗传学研究更有参考价值：方法：评估血浆（n = 2317）和脑脊液（n = 3107）中与 AD 相关的 11 种蛋白质（α-突触核蛋白、载脂蛋白 E [apoE]、CLU、GFAP、GRN、NfL、NRGN、SNAP-25、TREM2、VILIP-1、YKL-40）。对每种蛋白质都进行了血浆和脑脊液全基因组关联研究（GWAS）分析，然后进行了功能注释。每个生物标志物的其他特征包括相关性和预测力的计算：结果：确定了与 10 种蛋白质相关的 18 个血浆蛋白质定量训练基因座（pQTLs）和与 9 种蛋白质相关的 16 个脑脊液 pQTLs。血浆和脑脊液共享一些基因位点，但组织间的蛋白质水平相关性较弱。与血浆相比，CSF蛋白质水平与AD的相关性更好：讨论：本研究结果表明，在进行 AD 遗传学研究时，CSF 比血浆更有参考价值：在血浆和脑脊液（CSF）中发现了新的蛋白质定量性状位点（pQTLs）。血浆和脑脊液中神经变性相关蛋白质的水平相关性较弱。对于阿尔茨海默病（AD）的基因研究而言，脑脊液比血浆更有参考价值。神经丝蛋白（NfL）、髓样细胞上表达的触发受体2（TREM2）和几丁质酶-3样蛋白1（YKL-40）往往显示出相对较强的组织间关联。在载脂蛋白 E（APOE）区域发现了一个新信号，即 APOC1 的 eQTL。
A genetic and proteomic comparison of key AD biomarkers across tissues
INTRODUCTION
Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD.
METHOD
Eleven proteins associated with AD (α-synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP-25, TREM2, VILIP-1, YKL-40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome-wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power.
RESULTS
Eighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma.
DISCUSSION
The present results indicate that CSF is more informative than plasma for genetic studies in AD.
Highlights
The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF).
Plasma and CSF levels of neurodegeneration-related proteins correlated weakly.
CSF is more informative than plasma for genetic studies of Alzheimer's disease (AD).
Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40) tend to show relatively strong inter-tissue associations.
A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1.
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.
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