Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, Devon, UK.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, The Netherlands.
Alzheimers Dement. 2024 Oct;20(10):6722-6739. doi: 10.1002/alz.14098. Epub 2024 Aug 28.
We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration.
We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array.
We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development.
We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain.
Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.
我们研究了与阿尔茨海默病（AD）病理生理学、神经炎症和神经退行性变的 15 种成熟的脑脊液（CSF）生物标志物相关的血液 DNA 甲基化模式。
我们使用 EPIC 阵列评估了来自欧洲阿尔茨海默病医学信息框架（EMIF-AD）研究的 885 个血液样本的 DNA 甲基化。
我们确定了与 CSF YKL-40（五个位点）和神经丝轻链（NfL；七个位点）水平相关的 Bonferroni 显著差异甲基化，其中两个与 CSF YKL-40 水平相关的位点与 CSF YKL-40 水平相关的血浆 YKL-40 水平相关。共定位分析显示，YKL-40 DNA 甲基化和 CSF 蛋白水平的遗传变异存在共同作用，并且证据表明 DNA 甲基化介导了基因型与蛋白水平之间的关联。加权基因相关网络分析确定了与几种淀粉样蛋白测量值相关的两个共甲基化基因模块，并富集了与脂蛋白和发育相关的途径。
我们进行了迄今为止最全面的 AD 相关 CSF 生物标志物的全基因组关联研究（EWAS）。未来的工作应探索 YKL-40 基因型、DNA 甲基化和大脑中蛋白质水平之间的关系。
在 EMIF-AD MBD 研究中评估了血液 DNA 甲基化。对 15 种与阿尔茨海默病（AD）相关的脑脊液（CSF）生物标志物进行了全基因组关联研究（EWAS）。与 YKL-40 水平相关的有 5 个 Bonferroni 显著位点，与神经丝轻链（NfL）相关的有 7 个位点。YKL-40 中的 DNA 甲基化与先前报道的遗传变异部分重叠。DNA 甲基化可能介导 YKL-40 中的单核苷酸多态性（SNP）对 CSF 蛋白水平的影响。
