Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
Alzheimers Dement. 2021 Oct;17(10):1628-1640. doi: 10.1002/alz.12330. Epub 2021 May 14.
Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.
We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.
We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.
Our study provides important new insights into the genetic architecture underlying interindividual variation in three 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.
神经丝轻链（NfL）、几丁质酶-3 样蛋白 1（YKL-40）和神经颗粒蛋白（Ng）分别是用于监测轴突损伤、星形胶质细胞激活和突触退化的阿尔茨海默病（AD）的生物标志物。
我们使用来自 EMIF-AD 多模态生物标志物发现研究的 DNA 和脑脊液（CSF）样本进行了全基因组关联研究（GWAS），用于发现，并使用阿尔茨海默病神经影像学倡议研究进行了验证分析。使用线性回归模型对所有三种 CSF 生物标志物进行了 GWAS 分析，调整了相关协变量。
我们在 TMEM106B 的 DNA 变异与 NfL 的 CSF 水平之间，以及在 CPOX 和 YKL-40 之间，发现了与 DNA 变异与 CSF 水平之间存在新的全基因组显著关联。我们证实了先前的工作，表明 YKL-40 水平与 CHI3L1 中的 DNA 变异有关。
我们的研究为 AD 相关 CSF 生物标志物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启动和进展有关的事件顺序。
