Abstract
The CACNA1C and the ZNF804A genes are among the most relevant schizophrenia GWAS findings. Recent evidence shows that the interaction of these genes with the schizophrenia diagnosis modulates brain functional response to a verbal fluency task. To better understand how these genes might influence the risk for schizophrenia, we aimed to study the interplay between CACNA1C and ZNF804A on working memory brain functional correlates. The analyses included functional and behavioural N-back task data (obtained from an fMRI protocol) and CACNA1C-rs1006737 and ZNF804A-rs1344706 genotypes for 78 healthy subjects and 78 patients with schizophrenia (matched for age, sex and premorbid IQ). We tested the effects of the epistasis between these genes as well as of the three-way interaction (CACNA1C × ZNAF804A × diagnosis) on working memory-associated activity (N-back: 2-back vs 1-back). We detected a significant CACNA1C × ZNAF804A interaction on working memory functional response in regions comprising the ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula. The individuals with the GWAS-identified risk genotypes (CACNA1C-AA/AG and ZNF804A-AA) displayed a reduced working memory modulation response. This genotypic combination was also associated with opposite brain activity patterns between patients and controls. While further research will help to comprehend the neurobiological mechanisms of this interaction, our data highlight the role of the epistasis between CACNA1C and ZNF804A in the functional mechanisms underlying the pathophysiology of schizophrenia.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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The authors would like to thank the volunteers participating in the study.
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This study received project funding from: (i) the Instituto de Salud Carlos III through the projects PI15/01420 and PI18/01535, and through the contracts FI19/0352 to MG-R, CD19/00149 to PF-C and CP20/00072 to MF-V (co-funded by European Regional Development Fund (ERDF)/European Social Fund “Investing in your future”); (ii) The Health Department from the Generalitat de Catalunya through contract SLT017/20/000233 to AS-M; (iii) the Comissionat per a Universitats i Recerca del DIUE of the Generalitat de Catalunya (Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), 2017SGR1271).
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MF-V and MG-R conceived the study. MG-R, CA-P, AL and AS conducted the DNA extraction and genotyping. PS-P, JO-G, JJG, AG-P, SS and EP-C conducted the recruitment and/or the clinical evaluation. RS, TM and EP-C designed the MRI protocol and supervised the fMRI analyses. PS-P and PF-C pre-processed the fMRI images. MG-R, CA-P and MF-V performed the data curation and the statistical analyses. PF-C, RS and SP participated in the revision of the methodology. MG-R, CA-P and MF-V wrote the first draft and subsequent drafts of the paper. MG-R, CA-P and MF-V interpreted the results and revised the manuscript. MF-V supervised the study activity planning and execution. VM, EP-C and MF-V participated in the funding acquisition. All the authors reviewed and approved the final manuscript.
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Guardiola-Ripoll, M., Almodóvar-Payá, C., Lubeiro, A. et al. A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A). Eur Arch Psychiatry Clin Neurosci 272, 1229–1239 (2022). https://doi.org/10.1007/s00406-022-01447-z
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DOI: https://doi.org/10.1007/s00406-022-01447-z