A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A)

Guardiola-Ripoll, Maria; Almodóvar-Payá, Carmen; Lubeiro, Alba; Sotero, Alejandro; Salvador, Raymond; Fuentes‐Claramonte, Paola; Salgado‐Pineda, Pilar; Papiol, Sergi; Ortíz-Gil, Jordi; Gomar, Jesús J.; Guerrero-Pedraza, Amalia; Sarró, Salvador; Maristany, Teresa; Molina, Vicente; Pomarol‐Clotet, Edith; Fatjó‐Vilas, Mar

doi:10.1007/s00406-022-01447-z

Cited by 4 publications

(6 citation statements)

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“…This gene has also been associated with dorsolateral prefrontal cortex coupling with the hippocampus and prefrontal cortex (Rasetti et al 2011;Zhao et al 2020;Yang et al 2021). Finally, a recent study has identified a genetic interaction effect between CACNA1C and ZNF804A modulating the activity ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula during a working memory task (Guardiola-Ripoll et al 2022).…”

Section: Impact Of Neurodevelopmental Disturbances On Brain Connectiv...mentioning

confidence: 99%

“…The evidence of an effect on brain structure/volume of genetic variants in CACNA1C is weak due to the lack of convincing replication of original findings (Gurung and Prata 2015). However, literature regarding the functional effects of this gene is more consistent (Guardiola-Ripoll et al 2022). One of the most replicated findings is the influence of CACNA1C genetic variants on the connectivity between the dorsolateral prefrontal cortex and the hippocampus (Paulus et al 2014).…”

Section: Impact Of Neurodevelopmental Disturbances On Brain Connectiv...mentioning

confidence: 99%

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Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

2022

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Since more than 3 decades, schizophrenia (SZ) has been regarded as a neurodevelopmental disorder. The neurodevelopmental hypothesis proposes that SZ is associated with genetic and environmental risk factors, which influence connectivity in neuronal circuits during vulnerable developmental periods. We carried out a non-systematic review of genetic/environmental factors that increase SZ risk in light of its neurodevelopmental hypothesis. We also reviewed the potential impact of SZ-related environmental and genetic risk factors on grey and white matter pathology and brain function based on magnetic resonance imaging and post-mortem studies. Finally, we reviewed studies that have used patient-derived neuronal models to gain knowledge of the role of genetic and environmental factors in early developmental stages. Taken together, these studies indicate that a variety of environmental factors may interact with genetic risk factors during the pre- or postnatal period and/or during adolescence to induce symptoms of SZ in early adulthood. These risk factors induce disturbances of macro- and microconnectivity in brain regions involving the prefrontal, temporal and parietal cortices and the hippocampus. On the molecular and cellular level, a disturbed synaptic plasticity, loss of oligodendrocytes and impaired myelination have been shown in brain regions of SZ patients. These cellular/histological phenotypes are related to environmental risk factors such as obstetric complications, maternal infections and childhood trauma and genetic risk factors identified in recent genome-wide association studies. SZ-related genetic risk may contribute to active processes interfering with synaptic plasticity in the adult brain. Advances in stem cell technologies are providing promising mechanistic insights into how SZ risk factors impact the developing brain. Further research is needed to understand the timing of the different complex biological processes taking place as a result of the interplay between genetic and environmental factors.

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Section: Impact Of Neurodevelopmental Disturbances On Brain Connectiv...mentioning

confidence: 99%

Section: Impact Of Neurodevelopmental Disturbances On Brain Connectiv...mentioning

confidence: 99%

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

2022

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“…Indeed, some studies have shown that genetic effects on clinical phenotypes are mediated by speci c brain regions and functions in mental disorders (Sudre et al, 2020). Nevertheless, few cases in the literature explore the impact of epistasis on brain phenotypes (Callicott et al, 2013;Guardiola-Ripoll et al, 2022;Tecelão et al, 2019;Xu et al, 2018) and its mediation effect on clinical symptoms in SZ.…”

Section: Introductionmentioning

confidence: 99%

Nrn1 Epistasis With Bdnf and Cacna1c: Mediation Effects on Symptom Severity Through Neuroanatomical Changes in Schizophrenia

Almodóvar-Payá,

Guardiola-Ripoll,

Giralt-López

et al. 2024

Preprint

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The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1's activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on i) the risk for SZ, ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder's clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 × CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 × BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their meditation role in the path from genetics to complex clinical manifestation.

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“…A recent meta-analysis demonstrated an effect of CACNA1C rs1006737 polymorphism with cognitive function in patients with schizophrenia and bipolar disorder [ 9 ]. This issue presents an article by Guardiola-Ripoll et al [ 10 ] who detected a significant CACNA1C x ZNAF804A interaction on working memory-based functional response in the ventral caudate, the left superior and inferior orbitofrontal gyrus, the left superior temporal pole and the ventral–anterior insula. Future studies should investigate in more detail the neurobiological background of CACNA1C and CACNA1D risk polymorphisms in schizophrenia with a special focus on synaptic plasticity and cognitive impairment.…”

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confidence: 99%

Post-mortem gene expression of calcium channels Cav1.2 and Cav1.3 in schizophrenia

Schmitt

Uhrig

Spanagel

et al. 2022

Eur Arch Psychiatry Clin Neurosci

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A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A)

Cited by 4 publications

References 65 publications

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

Nrn1 Epistasis With Bdnf and Cacna1c: Mediation Effects on Symptom Severity Through Neuroanatomical Changes in Schizophrenia

Post-mortem gene expression of calcium channels Cav1.2 and Cav1.3 in schizophrenia

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