| 1. |
- Gracias, J., et al.
(author)
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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
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| 2. |
- Hörbeck, Elin, 1984, et al.
(author)
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Dissecting the impact of complement component 4A in bipolar disorder.
- 2023
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In: Brain, behavior, and immunity. - 1090-2139. ; 116, s. 150-159
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Journal article (peer-reviewed)abstract
- The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.
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| 3. |
- Koskuvi, Marja, et al.
(author)
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Lower complement C1q levels in first-episode psychosis and in schizophrenia
- 2024
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In: Brain, Behavior, and Immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 117, s. 313-319
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Journal article (peer-reviewed)abstract
- Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10-05), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications.
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| 4. |
- Smedler, Erik, et al.
(author)
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Association of premorbid intelligence with level of functioning and illness severity in bipolar disorder.
- 2023
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In: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 324, s. 449-454
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a severe psychiatric syndrome defined by periodic mood shifts. Patients with bipolar disorder show cognitive impairments relative to healthy controls. The risk of developing schizophrenia, and partially also bipolar disorder, has previously been shown to increase with lower premorbid intelligence. It is not known if premorbid intelligence is associated with level of functioning and illness severity of people having developed bipolar disorder.We used multiple linear and ordinal regression to analyze how premorbid intelligence, as measured at conscription, associate with functional outcome and illness severity in Swedish male bipolar disorder patients (n = 788).We found that lower premorbid intelligence is associated with lower percentage of time in work, after adjusting for age and bipolar subtype, and correcting for multiple comparisons. We also found a strong negative association with the total number of inpatient episodes and psychiatric comorbidity, but not with interepisodic remission, treatment with psychotherapy or lithium or the presence of any complicating socioeconomical factors. Adjusting for confounding genetic factors using polygenic risk scores for bipolar disorder and schizophrenia had no effect on the associations.This study lacks females and controls and may thus have lower generalizability.In conclusion, premorbid intelligence is associated with both level of functioning and illness severity as well as comorbidity in bipolar disorder patients. Further research is needed to develop targeted interventions for this subgroup of bipolar disorder patients.
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