PubMed · 13558955
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A FAURBYE, I MUNKVAD, K PIND. 1958. The thyroid function in chronic schizophrenia (hebephrenia).. https://doi.org/10.1530/acta.0.0280395
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In patients with schizophrenia we found that genes and dark genome disconnect. This opens new areas for possible diagnostics and treatments.
Schizophrenia (SCZ) is a common psychiatric disorder with a complex, genetically and environmentally influenced etiology, but the specific pathogenesis remains unclear. In recent years, the SCZ susceptibility gene CNNM2 (encoding cyclin M2) located at the 10q24.32-33 locus has received widespread attention. The well-validated SCZ risk interval 10q24.32-33 harbors two independent risk variants: rs11191580 in NT5C2 (significantly associated with CNNM2 mRNA and protein levels) and rs7914558 in CNNM2. Results from functional genomic analyses indicate that lower CNNM2 expression is significantly associated with SCZ. Imaging genetics studies have demonstrated that carriers of risk alleles of CNNM2 SNPs exhibit alterations in brain structure. Animal model studies have revealed that Cnnm2 downregulation in mice leads to impairments in sensorimotor gating and cognitive function. As an Mg2+ transporter, CNNM2 primarily maintains systemic Mg2+ homeostasis. According to clinical studies, a proportion of patients with SCZ exhibit reduced Mg2+ concentrations in plasma and cerebrospinal fluid. CNNM2 dysfunction may contribute to the pathology of SCZ by disrupting Mg2+ homeostasis, thereby affecting neurodevelopment and synaptic plasticity. A systematic consolidation of current evidence supporting the involvement of CNNM2 in SCZ pathogenesis provides a direction for further investigation of the pathological mechanisms underlying this disease, and for identification of novel targets for clinical intervention..
BACKGROUND: Schizophrenia and immune-mediated diseases are globally prevalent and highly heritable conditions that frequently co-occur, posing major public health burdens. However, their shared genetic architecture remains poorly understood. METHODS: We applied the bivariate causal mixture model (MiXeR) to investigate the polygenic overlap between schizophrenia and eight common immune-mediated diseases, using genome-wide association study summary statistics comprising 2,489 to 67,323 cases and 9,066 to 497,622 controls. Shared loci were identified through conditional/conjunctional false discovery rate (cond/conjFDR), local genetic correlation (LAVA), and colocalization analyses. Subsequently, gene mapping, functional annotation, expression-trait association, and drug-gene interaction analyses were performed to explore shared genes and enriched pathways, and genetic risk scores (GRS) from the UK Biobank were used to validate the findings. RESULTS: MiXeR estimated substantial polygenic overlap between schizophrenia and immune-mediated diseases, and conjFDR identified 133 shared loci, with eight prioritized through local genetic correlation and colocalization signals. These eight loci were mapped to 85 protein-coding genes enriched in pathways essential for B cell function. Among them, S-PrediXcan analyses identified 14 genes whose expression in brain tissues or blood was associated with both diseases. These genes also interact with immunomodulatory or antihypertensive drugs. Additionally, 11 of the 14 genes were linked to innate immunity and/or cognitive traits. Using UK Biobank data, we further confirmed that overall, shared gene, and B cell activation and receptor signaling pathway–specific genetic risk for schizophrenia is associated with immune-mediated disease susceptibility. CONCLUSIONS: These findings underscore the shared genetic architecture of schizophrenia and immune-mediated diseases, advancing insights at the interface of psychiatric genetics and immunology.