NRN1 epistasis with BDNF and CACNA1C : mediation effects on symptom severity through neuroanatomical changes in schizophrenia
Almodóvar-Payá, Carmen (Instituto de Salud Carlos III)
Guardiola-Ripoll, Maria (Instituto de Salud Carlos III)
Giralt López, Maria (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Oscoz-Irurozqui, Maitane (Red de Salud Mental de Gipuzkoa)
Canales-Rodriguez, Erick Jorge (École Polytechnique Fédérale de Lausanne (EPFL))
Madre Rull, Mercè (Institut de Recerca Sant Pau)
Soler-Vidal, Joan (Hospital Benito Menni)
Ramiro, Núria (Hospital San Rafael)
Callado, Luis F. (Universidad del País Vasco)
Arias, Bárbara (Universitat de Barcelona)
Gallego, Carme (Institut de Biologia Molecular de Barcelona)
Pomarol-Clotet, Edith (Instituto de Salud Carlos III)
Fatjó-Vilas, Mar (Instituto de Salud Carlos III)
Universitat Autònoma de Barcelona

Data:	2024
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Genetic epistasis ; Mediation ; Neuroimaging ; Schizophrenia ; Symptoms
Publicat a:	Brain Structure and Function, Vol. 229 Núm. 5 (june 2024) , p. 1299-1315, ISSN 1863-2661

DOI: 10.1007/s00429-024-02793-5
PMID: 38720004
PMID: 38720004

17 p, 1.9 MB

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