Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer’s disease, GPNMB and Parkinson’s disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.

尽管神经系统疾病的全球负担不断增加，但仍缺乏有效的诊断和治疗生物标志物。蛋白质通常在疾病中失调并且具有很强的遗传成分。在这里，我们使用来自两个孤立的基于人群的队列的全基因组测序数据，对 184 种神经学相关蛋白质进行了蛋白质数量性状位点分析（N = 2893）。通过这样做，我们阐明了循环蛋白质组的遗传景观及其与神经系统疾病的联系。我们检测到 107 种蛋白质的 214 种独立相关变体，其中大部分 (76%) 是顺式作用的，包括 114 种以前未发现的变体。使用双样本孟德尔随机化，我们确定了血清 CD33 与阿尔茨海默病、GPNMB 与帕金森病以及 MSR1 与精神分裂症之间的因果关系，描述了它们的临床潜力并强调了药物再利用的机会。