Background

Genome-wide association studies have identified multiple risk variants for psychiatric disorders. Nevertheless, how the risk variants confer risk of psychiatric disorders remains largely unknown.

Methods

We performed proteome-wide association studies to identify genes whose cis-regulated protein abundance change in the human brain were associated with psychiatric disorders.

Results

By integrating genome-wide associations of four common psychiatric disorders and two independent brain proteomes (n = 376 and n = 152, respectively) from the dorsolateral prefrontal cortex, we identified 61 genes (including 48 genes for schizophrenia, 12 genes for bipolar disorder, 5 genes for depression, and 2 genes for attention-deficit/hyperactivity disorder) whose genetically regulated protein abundance levels were associated with risk of psychiatric disorders. Comparison with transcriptome-wide association studies identified 18 overlapping genes that showed significant associations with psychiatric disorders at both proteome-wide and transcriptome-wide levels, suggesting that genetic risk variants likely confer risk of psychiatric disorders by regulating messenger RNA expression and protein abundance of these genes.

Conclusions

Our study not only provides new insights into the genetic component of protein abundance in psychiatric disorders but also highlights several high-confidence risk proteins (including CNNM2 and CTNND1) for schizophrenia and depression. These high-confidence risk proteins represent promising therapeutic targets for future drug development.

中文翻译：

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全蛋白质组关联研究提供了对精神疾病蛋白质丰度遗传成分的见解

背景

全基因组关联研究已经确定了精神疾病的多种风险变异。然而，风险变异如何赋予精神疾病风险在很大程度上仍然未知。

方法

我们进行了全蛋白质组关联研究，以确定人类大脑中顺式调节蛋白质丰度变化与精神疾病相关的基因。

结果

通过整合四种常见精神疾病和两种独立大脑蛋白质组的全基因组关联（n  = 376 和n = 152，分别来自背外侧前额叶皮层，我们确定了 61 个基因（包括 48 个精神分裂症基因、12 个双相情感障碍基因、5 个抑郁症基因和 2 个注意力缺陷/多动障碍基因），其基因调节蛋白质丰度水平与精神疾病的风险有关。与全转录组关联研究的比较确定了 18 个重叠基因，这些基因在全蛋白质组和全转录组水平上均与精神疾病显着相关，这表明遗传风险变异可能通过调节这些基因的信使 RNA 表达和蛋白质丰度来赋予精神疾病风险基因。

结论

我们的研究不仅为精神疾病中蛋白质丰度的遗传成分提供了新的见解，而且还突出了精神分裂症和抑郁症的几种高置信风险蛋白质（包括 CNNM2 和 CTNND1）。这些高置信度风险蛋白代表了未来药物开发的有希望的治疗靶点。