Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
Nat Commun. 2021 Dec 2;12(1):7042. doi: 10.1038/s41467-021-27387-1.
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.
尽管神经疾病的全球负担不断增加，但缺乏有效的诊断和治疗生物标志物。蛋白质在疾病中经常失调，并且具有很强的遗传成分。在这里，我们使用来自两个独立基于人群的队列（N=2893）的全基因组测序数据，对 184 种与神经相关的蛋白质进行蛋白质数量性状基因座分析。通过这种方式，我们阐明了循环蛋白质组的遗传景观及其与神经疾病的联系。我们检测到 107 种蛋白质的 214 个独立相关变体，其中大多数（76%）是顺式作用的，包括 114 个以前未被识别的变体。使用两样本孟德尔随机化，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联，描述了它们的临床潜力，并强调了药物重新定位的机会。
