Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

表征甲基化组、蛋白质组和表型组之间的关联可能有助于深入了解控制大脑健康的生物学途径。在这里，我们报告了与大脑健康相关的循环蛋白质组的综合 DNA 甲基化和表型研究。对 4058 种血浆蛋白进行了全甲基化关联研究 ( N  = 774)，在调整多次测试后确定了 2928 种 CpG 蛋白关联。这些与已知的遗传蛋白数量性状基因座 (pQTL) 和常见的生活方式影响无关。然后针对 15 种神经学特征（ N = 1,065）对每种蛋白质进行全表型关联研究 ，确定 191 种蛋白质水平与认知评分、脑成像测量或APOE之间的 405 种关联e4 状态。我们发现了 35 个以前未报道的关于 17 种大脑健康蛋白质标志物的 DNA 甲基化特征。我们确定的表观遗传和蛋白质组学标记与理解和分层大脑健康有关。