Changes in immune function are associated with variance in cognitive functioning in schizophrenia. Given that microglia are the primary innate immune cells in the brain, we examined whether schizophrenia risk-associated microglial genes (measured via polygenic score analysis) explained variation in cognition in patients with schizophrenia and controls (n = 1,238) and tested whether grey matter mediated this association. We further sought to replicate these associations in an independent sample of UK Biobank participants (n = 134,827). We then compared the strength of these microglial associations to that of neuronal and astroglial (i.e., other brain-expressed genes) polygenic scores, and used MAGMA to test for enrichment of these gene-sets with schizophrenia risk. Increased microglial schizophrenia polygenic risk was associated with significantly lower performance across several measures of cognitive functioning in both samples; associations which were then found to be mediated via total grey matter volume in the UK Biobank. Unlike neuronal genes which did show evidence of enrichment, the microglial gene-set was not significantly enriched for schizophrenia, suggesting that the relevance of microglia may be for neurodevelopmental processes related more generally to cognition. Further, the microglial polygenic score was associated with performance on a range of cognitive measures in a manner comparable to the neuronal schizophrenia polygenic score, with fewer cognitive associations observed for the astroglial score. In conclusion, our study supports the growing evidence of the importance of immune processes to understanding cognition and brain structure in both patients and in the healthy population.

免疫功能的变化与精神分裂症认知功能的变化有关。鉴于小胶质细胞是大脑中主要的先天免疫细胞，我们检查了与精神分裂症风险相关的小胶质细胞基因（通过多基因评分分析测量）是否可以解释精神分裂症患者和对照组（n  = 1,238）的认知差异，并测试灰质是否介导这个协会。我们进一步试图在英国生物银行参与者的独立样本中复制这些关联（n  = 134,827）。然后，我们将这些小胶质细胞关联的强度与神经元和星形胶质细胞（即其他大脑表达基因）多基因评分的强度进行比较，并使用 MAGMA 来测试这些基因集与精神分裂症风险的富集情况。小胶质细胞精神分裂症多基因风险的增加与两个样本中多项认知功能指标的表现显着降低有关；随后在英国生物库中发现这种关联是通过总灰质体积介导的。与确实显示富集证据的神经元基因不同，小胶质细胞基因集在精神分裂症中并未显着富集，这表明小胶质细胞的相关性可能与更广泛地与认知相关的神经发育过程相关。此外，小胶质细胞多基因评分与一系列认知测量的表现相关，其方式与神经元精神分裂症多基因评分相当，而星形胶质细胞评分观察到的认知关联较少。总之，我们的研究支持越来越多的证据表明免疫过程对于理解患者和健康人群的认知和大脑结构的重要性。