Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936
Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936
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DOI：
10.1038/s41467-019-11177-x
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发表时间：
2019-07-18
影响因子：
16.6
通讯作者：
Marioni, Riccardo E.
中科院分区：
文献类型：
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作者：
Hillary, Robert F.;McCartney, Daniel L.;Marioni, Riccardo E.
虽然血浆蛋白可以作为神经系统疾病风险的标志物，但对血浆蛋白水平个体间差异的分子机制知之甚少。因此，我们对92种神经蛋白水平进行了全基因组和表观基因组关联研究，以确定与其血浆浓度相关的遗传和表观遗传位点（n = 750名健康老年人）。我们鉴定了33种蛋白质的41个独立全基因组显著位点（P < 5.4 x 10(-10)）和与9种蛋白质水平相关的26个表观全基因组显著位点（P < 3.9 x 10(-10)）。利用这些信息，我们确定了涉及假定的神经生物标志物的生物学途径（神经学、免疫学和细胞外基质代谢途径）。我们还观察了基因表达（DRAXIN， MDGA1和KYNU）或DNA甲基化谱（MATN3， MDGA1和NEP）变化与血浆蛋白水平改变之间的因果关系（通过孟德尔随机化分析）。总之，这可能有助于了解生物标志物和神经系统疾病之间的因果关系。
Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 x 10(-10)) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 x 10(-10)) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.