Leveraging high-dimensional molecular datasets can help us develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Furthermore, genetic colocalization provided evidence that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotype. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system (p = 4.29 × 10⁻¹¹ with neuroticism), as well as SARM1, which has been previously implicated in axonal degeneration (p = 1.76 × 10⁻⁰⁸ with amyotrophic lateral sclerosis). We additionally conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases. Our findings suggest that genes such as SNX32, which was initially associated with increased risk of Alzheimer disease, may potentially influence other complex traits in the opposite direction. In contrast, genes such as CTSH (which was also associated with Alzheimer disease) and SARM1 may make worthwhile therapeutic targets because they did not have genetically predicted effects on any of the other phenotypes after correcting for multiple testing.

利用高维分子数据集可以帮助我们深入了解遗传变异和复杂性状之间的关联。在这项研究中，我们整合了来自脑组织的人类蛋白质组数据，以评估目标蛋白质是否介导遗传变异对七种神经表型（阿尔茨海默病、肌萎缩侧索硬化症、抑郁症、失眠、智力、神经质和精神分裂症）的影响。在整个基因组中系统地应用孟德尔随机化 (MR) 原理，突出了源自背外侧前额叶皮层的基因预测蛋白质与这些结果之间的 43 种影响。此外，遗传共定位提供的证据表明，其中 12 个位点的相同因果变异导致了蛋白质和神经表型的变异。这包括DCC等基因，它编码 netrin-1 受体，在神经系统的发育中具有重要作用（神经质时 p = 4.29 × 10 ⁻¹¹ ），以及SARM1，之前与轴突有关变性（p = 1.76 × 10 ^-08伴有肌萎缩侧索硬化症）。我们还对这 12 个基因中的每一个进行了全表型 MR 研究，以评估对 700 种复杂性状和疾病的潜在多效性影响。我们的研究结果表明， SNX32等基因最初与阿尔茨海默病风险增加有关，但可能会以相反的方向影响其他复杂性状。 相比之下， CTSH （也与阿尔茨海默病有关）和SARM1等基因可能成为有价值的治疗靶点，因为在校正多重测试后，它们对任何其他表型都没有基因预测的影响。