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Open Access 09-05-2024 | Schizophrenia | Original Article

NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia

Authors: Carmen Almodóvar-Payá, Maria Guardiola-Ripoll, Maria Giralt-López, Maitane Oscoz-Irurozqui, Erick Jorge Canales-Rodríguez, Mercè Madre, Joan Soler-Vidal, Núria Ramiro, Luis F. Callado, Bárbara Arias, Carme Gallego, Edith Pomarol-Clotet, Mar Fatjó-Vilas

Published in: Brain Structure and Function | Issue 5/2024

Abstract

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 (SZ) 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 x 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 x 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 mediation role in the path from genetics to complex clinical manifestation.

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Title: NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia
Authors: Carmen Almodóvar-Payá
Maria Guardiola-Ripoll
Maria Giralt-López
Maitane Oscoz-Irurozqui
Erick Jorge Canales-Rodríguez
Mercè Madre
Joan Soler-Vidal
Núria Ramiro
Luis F. Callado
Bárbara Arias
Carme Gallego
Edith Pomarol-Clotet
Mar Fatjó-Vilas
Publication date: 09-05-2024
Publisher: Springer Berlin Heidelberg
Keyword: Schizophrenia
Published in: Brain Structure and Function / Issue 5/2024
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-024-02793-5

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