Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Mol Genet Genomic Med. 2022 Jun;10(6):e1942. doi: 10.1002/mgg3.1942. Epub 2022 Apr 30.
Cognitive dysfunction is a core manifestation of schizophrenia and one of the best predictors of long-term disability. Genes increasing risk for schizophrenia may partly act through the modulation of cognition.
We imputed the expression of 130 genes recently prioritized for association with schizophrenia, using PsychENCODE variant weights and genotypes of patients with schizophrenia in CATIE. Processing speed, reasoning, verbal memory, working memory, vigilance, and a composite cognitive score were used as phenotypes. We performed linear regression models for each cognitive measure and gene expression score, adjusting for age, years of education, antipsychotic treatment, years since the first antipsychotic treatment and population principal components.
We included 425 patients and expression scores of 91 genes (others had no heritable expression; Bonferroni corrected alpha = 5.49e-4). No gene expression score was associated with cognitive measures, though ENOX1 expression was very close to the threshold for verbal memory (p = 6e-4) and processing speed (p = 7e-4). Other genes were nominally associated with multiple phenotypes (MAN2A1 and PCGF3).
A better understanding of the mechanisms mediating cognitive dysfunction in schizophrenia may help in the definition of disease prognosis and in the identification of new treatments, as the treatment of cognitive impairment remains an unmet therapeutic need.
认知功能障碍是精神分裂症的核心表现之一，也是长期残疾的最佳预测指标之一。增加精神分裂症风险的基因可能部分通过调节认知起作用。
我们使用 PsychENCODE 变体权重和 CATIE 中精神分裂症患者的基因型，对最近与精神分裂症相关的 130 个基因的表达进行了推断。使用处理速度、推理、言语记忆、工作记忆、警觉性和综合认知评分作为表型。我们对每个认知测量和基因表达评分进行了线性回归模型，调整了年龄、受教育年限、抗精神病药物治疗、首次抗精神病药物治疗后年限和人群主成分。
我们纳入了 425 名患者和 91 个基因的表达评分（其他基因没有可遗传的表达；Bonferroni 校正的 alpha 值为 5.49e-4）。没有基因表达评分与认知测量相关，尽管 ENOX1 表达非常接近言语记忆（p = 6e-4）和处理速度（p = 7e-4）的阈值。其他基因与多种表型呈名义相关（MAN2A1 和 PCGF3）。
更好地了解介导精神分裂症认知功能障碍的机制可能有助于定义疾病预后，并确定新的治疗方法，因为治疗认知障碍仍然是一个未满足的治疗需求。
