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TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
bioRxiv - Genomics Pub Date : 2020-06-01 , DOI: 10.1101/2020.05.31.125633
Shengjun Hong , Valerija Dobricic , Isabelle Bos , Stephanie J. B. Vos , Dmitry Prokopenko , Betty M. Tijms , Ulf Andreasson , Kaj Blennow , Rik Vandenberghe , Silvy Gabel , Philip Scheltens , Charlotte E. Teunissen , Sebastiaan Engelborghs , Giovanni Frisoni , Olivier Blin , Jill C. Richardson , Regis Bordet , Alberto Lleó , Daniel Alcolea , Julius Popp , Christopher Clark , Gwendoline Peyratout , Pablo Martinez-Lage , Mikel Tainta , Richard J. B. Dobson , Cristina Legido-Quigley , Kristel Sleegers , Christine Van Broeckhoven , Rudolph E Tanzi , Mara ten Kate , Michael Wittig , Andre Franke , Frederik Barkhof , Simon Lovestone , Johannes Streffer , Henrik Zetterberg , Pieter Jelle Visser , Lars Bertram

Background: Neurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimer's disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. Methods: DNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates. Findings: We identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. Interpretation: Our study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

中文翻译:

TMEM106B和CPOX是脑脊液阿尔茨海默氏病生物标志物水平的遗传决定因素

背景:神经丝光(NF-L),几丁质酶3样蛋白1(YKL-40)和神经颗粒蛋白(Ng)被用作阿尔茨海默氏病(AD)的生物标志物,以监测轴突损伤,星形胶质细胞活化和突触变性。 , 分别。在这里,我们使用所有三个生物标记物作为结果进行了全基因组关联研究(GWAS)分析。方法:DNA和脑脊液(CSF)样品源自欧洲医学信息框架AD多峰生物标志物发现(EMIF-AD MBD)研究。重叠的基因型/表型数据可用于n = 671(NF-L),677(YKL-40)和672(Ng)个体。GWAS分析应用的线性回归模型,对相关协变量进行调整。发现:我们确定与TMEM106B和NF-L的CSF水平中的标志物存在新的全基因组显着关联。在CPKL和CSF中,YKL-40的DNA变体还观察到其他新​​信号。最后,我们证实了先前的工作,表明YKL-40水平受CHI3L1中的顺式蛋白质定量性状基因座(pQTL)调控。解释:我们的研究为所有三种与AD相关的CSF生物标志物个体间变异背后的遗传结构提供了重要的新见解。特别是,我们的数据阐明了与AD相关的神经病理学过程的发生和发展的事件序列。我们的研究为所有三种经过测试的与AD相关的CSF生物标记物中个体间变异的遗传结构提供了重要的新见解。特别是,我们的数据阐明了与AD相关的神经病理学过程的发生和发展的事件序列。我们的研究为所有三种经过测试的与AD相关的CSF生物标志物个体间变异背后的遗传结构提供了重要的新见解。特别是,我们的数据阐明了与AD相关的神经病理学过程的发生和发展的事件序列。
更新日期:2020-06-01
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