Chen Xiongying, Zhang Qiumei, Su Yanyan, Zhao Wan, Li Yang, Du Boqi, Deng Xiaoxiang, Ji Feng, Dong Qi, Chen Chuansheng, Li Jun
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, P.R. China.
School of Public Health, Jining Medical University, Jining, Shandong Province, P.R. China.
Schizophrenia (Heidelb). 2022 Aug 20;8(1):66. doi: 10.1038/s41537-022-00271-7.
Gene HCN1 polymorphism (rs1501357) has been proposed to be one of the candidate risk genes for schizophrenia in the second report of the Psychiatric Genomics Consortium-Schizophrenia Workgroup. Although animal studies repeatedly showed a role of this gene in working memory, its contribution to working memory in human samples, especially in schizophrenia patients, is still unknown. To explore the association between rs1501357 and working memory at both behavioral (Study 1) and neural (Study 2) levels, the current study involved two independent samples. Study 1 included 876 schizophrenia patients and 842 healthy controls, all of whom were assessed on a 2-back task, a dot pattern expectancy task (DPX), and a digit span task. Study 2 included 56 schizophrenia patients and 155 healthy controls, all of whom performed a 2-back task during functional magnetic resonance imaging (fMRI) scanning. In both studies, we consistently found significant genotype-by-diagnosis interaction effects. For Study 1, the interaction effects were significant for the three tasks. Patients carrying the risk allele performed worse than noncarriers, while healthy controls showed the opposite pattern. For Study 2, the interaction effects were observed at the parietal cortex and the medial frontal cortex. Patients carrying the risk allele showed increased activation at right parietal cortex and increased deactivation at the medial frontal cortex, while healthy controls showed the opposite pattern. These results suggest that the contributions of rs1501357 to working memory capability vary in different populations (i.e., schizophrenia patients vs. healthy controls), which expands our understanding of the functional impact of the HCN1 gene. Future studies should examine its associations with other cognitive functions.
在精神基因组学联盟精神分裂症工作组的第二份报告中，基因HCN1多态性（rs1501357）被认为是精神分裂症的候选风险基因之一。尽管动物研究反复表明该基因在工作记忆中起作用，但其对人类样本尤其是精神分裂症患者工作记忆的影响仍不清楚。为了在行为（研究1）和神经（研究2）水平上探索rs1501357与工作记忆之间的关联，本研究纳入了两个独立样本。研究1包括876名精神分裂症患者和842名健康对照，所有参与者均接受了2-back任务、点模式预期任务（DPX）和数字广度任务的评估。研究2包括56名精神分裂症患者和155名健康对照，所有参与者在功能磁共振成像（fMRI）扫描期间执行2-back任务。在两项研究中，我们均一致发现显著的基因型与诊断交互作用效应。对于研究1，三项任务的交互作用效应均显著。携带风险等位基因的患者表现比非携带者差，而健康对照则呈现相反模式。对于研究2，在顶叶皮层和内侧前额叶皮层观察到交互作用效应。携带风险等位基因的患者右侧顶叶皮层激活增加，内侧前额叶皮层失活增加，而健康对照则呈现相反模式。这些结果表明，rs1501357对工作记忆能力的影响在不同人群（即精神分裂症患者与健康对照）中有所不同，这扩展了我们对HCN1基因功能影响的理解。未来的研究应考察其与其他认知功能的关联。
