FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
CIBERSAM (Biomedical Research Network in Mental Health, Instituto de Salud Carlos III), Madrid, Spain.
Eur Arch Psychiatry Clin Neurosci. 2022 Oct;272(7):1229-1239. doi: 10.1007/s00406-022-01447-z. Epub 2022 Jul 7.
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.
CACNA1C 和 ZNF804A 基因是精神分裂症 GWAS 最相关的发现之一。最近的证据表明，这些基因与精神分裂症诊断的相互作用调节了大脑对言语流畅性任务的功能反应。为了更好地理解这些基因如何影响精神分裂症的风险，我们旨在研究 CACNA1C 和 ZNF804A 之间的相互作用对工作记忆大脑功能相关性的影响。分析包括功能和行为 N 回任务数据（从 fMRI 方案中获得）以及 78 名健康受试者和 78 名精神分裂症患者（年龄、性别和前病智商匹配）的 CACNA1C-rs1006737 和 ZNF804A-rs1344706 基因型。我们测试了这些基因之间的上位性效应以及三因素相互作用（CACNA1C×ZNF804A×诊断）对与工作记忆相关的活动（N 回：2 回与 1 回）的影响。我们在包括腹侧尾状核中部和左半球、上和下眶额回、上颞极和腹前岛的区域中检测到工作记忆功能反应的显著 CACNA1C×ZNF804A 相互作用。具有 GWAS 确定的风险基因型（CACNA1C-AA/AG 和 ZNF804A-AA）的个体显示出工作记忆调节反应减少。这种基因型组合也与患者和对照组之间相反的大脑活动模式相关。虽然进一步的研究将有助于理解这种相互作用的神经生物学机制，但我们的数据强调了 CACNA1C 和 ZNF804A 之间的上位性在精神分裂症病理生理学的功能机制中的作用。
