Abstract
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.
Highlights
Schizophrenia (SZ) is a complex neuropsychiatric disorder in which the level of disability is strongly predicted by impairments in cognitive function
The observed direction of effect was that greater microglial SZ-Polygenic score (PGS) was associated with a decrease in cognitive performance
When examining other gene cell types expressed in the brain, we. This is the first genetic study to associate found that the neuronal SZ-PGS was, as expected, signifivariation in a microglial-expressed gene-set to cognitive perfor- cantly associated with measures of cognitive performance
Summary
Schizophrenia (SZ) is a complex neuropsychiatric disorder in which the level of disability is strongly predicted by impairments in cognitive function. Genome-wide association studies (GWAS) have demonstrated that the immune system may be involved in these interactions, largely due to the strong association of genetic variants in the major histocompatibility complex (MHC) [1, 2]. The MHC region encodes ~230 genes and is associated with immune function. Variation of the complement component 4 (C4) gene has been associated with SZ risk [3]; we recently demonstrated that genetically predicted higher C4 expression was associated with both reduced memory function and reduced cortical activation [4]. We have further shown that these cognitive and cortical associations appear to generalise to genetic risk variants in the complement pathway more broadly [5, 6]. Complement protein expression has been linked with an increased risk of transition from a high-risk state to psychosis [7]
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