Background

Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods

General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment.

Results

A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = −0.66, 95% confidence interval [CI] = −1.31 to −0.01) and replication samples (β = −0.91, 95% CI = −1.71 to −0.11) and after meta-analysis (β = −0.76, 95% CI = −1.26 to −0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = −0.15, 95% CI = −0.29 to −0.001, p = .048).

Conclusions

In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5–1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.

中文翻译：

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罕见的拷贝数变异与精神分裂症的较差认知有关

背景

精神分裂症的认知障碍是导致不良结果的主要原因，但对其原因知之甚少。一些罕见的拷贝数变异 (CNV) 与精神分裂症风险相关并影响健康人群的认知，但尚未研究它们对精神分裂症认知障碍的影响。我们检查了 12 种精神分裂症 CNV 对精神分裂症患者认知的影响。

方法

一般认知能力是使用测量和治疗研究改善精神分裂症认知的综合z评分在 875 名精神分裂症患者和 519 名精神分裂症患者的复制样本中使用 Wechsler 成人智力量表全量 IQ 进行的。使用线性回归，我们测试了认知与精神分裂症 CNV 状态之间的关联，以及年龄和性别的共变。此外，我们测试了 CNV 在精神分裂症富集基因组（功能丧失不耐受和突触基因组）中的基因是否与认知障碍相关。

结果

共鉴定出 23 名精神分裂症 CNV 携带者。在发现（β = -0.66, 95% 置信区间 [CI] = -1.31 至 -0.01）和复制样本（β = -0.91, 95% CI = -1.71 至-0.11) 和荟萃分析后 (β = -0.76, 95% CI = -1.26 至 -0.25, p  = .003)。击中功能丧失不耐受基因的 CNV 与认知能力下降相关（β = -0.15, 95% CI = -0.29 至 -0.001, p  = .048）。

结论

在精神分裂症患者中，精神分裂症 CNV 携带者的认知能力比非 CNV 携带者低 0.5-1.0 个标准差，这可能对临床评估和管理产生影响。我们还证明，罕见的 CNVs 击中对功能丧失变异不耐受的基因会导致更严重的认知障碍，超出已知的精神分裂症 CNVs 的影响。