Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

Abstract

BackgroundPrevious studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.AimsTo detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia.MethodThe analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia.ResultsPatients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61–5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only.ConclusionsThe pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.Declaration of interestsNone.

Neuroimaging-based brain-age prediction of first-episode schizophrenia and the alteration of brain age after early medication

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Acute conceptual disorganization in untreated first-episode psychosis: a combined magnetic resonance spectroscopy and diffusion imaging study of the cingulum

“…Our findings suggest that the severity of CD in untreated FEP may be related to markers of oxidative stress and white matter damage, but not to glutamate deficits as indexed using MRS. Our observation of reduced white matter integrity of the cingulum in patients with high CD was consistent with the findings of Bopp and colleagues, 7 who systematically studied white matter integrity in relation to persistent disorganization. Reduced white matter integrity in the cingulum is a well-replicated finding in psychotic disorders, 22,[67][68][69] although heterogeneous changes are often reported at the whole brain level. 70 The cingulum is a large body of fibre connecting multiple midline brain regions that play a crucial role in selfrelated processing (precuneus, ventromedial prefrontal cortex and medial temporal cortex).…”

Predicting Epigenomic Functions of Genetic Variants in the Context of Neurodevelopment via Deep Transfer Learning

“…IRF3 is a key regulator of the innate immune system and is a plausible SCZ risk gene [88]. Recent studies show that it may be important in regulating the development of neuronal progenitor cells [48], and physically interacts with other schizophrenia susceptibility genes, such as CREB1, AKT1 and ESR1 [88]. We performed additional in-depth study of a region containing rs1080500, which is highlighted as possible causal variant by MetaChrom.…”

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