Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate <5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

精神疾病具有高度遗传性，但具有多基因性，可能涉及数百个风险基因。全基因组关联研究已经确定了数百个对精神疾病易感的基因组易感位点；然而，这些基因座对潜在的精神病理学和病因学的贡献仍然难以捉摸。在这里，我们使用 11 重串联质量标签结合二维液相色谱-串联质谱法对 268 名受试者的 11,608 种蛋白质进行定量，生成了深层人脑蛋白质组学数据。我们的分析揭示了 788 个顺式作用蛋白数量性状位点与 883 个蛋白的表达相关，全基因组错误发现率 <5%。与转录水平的表达和主要受非编码变异影响的复杂疾病相比，我们发现蛋白质表达水平往往受到非同义变异的调节。我们还提供了基因表达和蛋白质丰度之间 76 个共享调控信号的证据。中介分析显示，对于大多数（88%）共定位基因，其相应蛋白的表达水平通过基因转录受到顺式-pQTL的调节。使用基于汇总数据的孟德尔随机化分析，我们确定了与精神分裂症有因果关系的 4 种蛋白质和 19 种基因。我们进一步将多个组学数据与网络分析相结合，以优先考虑精神分裂症风险位点的候选基因。总的来说，我们的研究结果强调了全蛋白质组连锁分析在获得精神疾病发病机制的机制见解方面的潜力。