一种与精神分裂症风险相关的miR-137生物途径与人脑情绪处理有关。

A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

作者信息

Pergola Giulio, Rampino Antonio, Sportelli Leonardo, Borcuk Christopher James, Passiatore Roberta, Di Carlo Pasquale, Marakhovskaia Aleksandra, Fazio Leonardo, Amoroso Nicola, Castro Mariana Nair, Domenici Enrico, Gennarelli Massimo, Khlghatyan Jivan, Kikidis Gianluca Christos, Lella Annalisa, Magri Chiara, Monaco Alfonso, Papalino Marco, Parihar Madhur, Popolizio Teresa, Quarto Tiziana, Romano Raffaella, Torretta Silvia, Valsecchi Paolo, Zunuer Hailiqiguli, Blasi Giuseppe, Dukart Juergen, Beaulieu Jean Martin, Bertolino Alessandro

机构信息

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.

出版信息

Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Mar;9(3):356-366. doi: 10.1016/j.bpsc.2023.11.001. Epub 2023 Nov 22.

DOI:10.1016/j.bpsc.2023.11.001

PMID:38000716

Abstract

BACKGROUND

miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing.

METHODS

Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n = 214; n = 136; n = 2075; n = 1800) and with short-term treatment response in patients with schizophrenia (N = 427).

RESULTS

In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n, n, n) in interaction with age (n); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia.

CONCLUSIONS

The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

摘要

背景

miR-137是一种参与大脑发育的微小RNA，可调节神经发生和神经元成熟。全基因组关联研究表明miR-137与精神分裂症风险有关，但并未解释其在脑功能和潜在生物学过程中的作用。由miR-137靶标介导的精神分裂症多基因风险与工作记忆相关，尽管其他证据指向情绪加工。我们在区分先前报道的miR-137靶标与工作记忆和情绪加工的关联的同时，对与精神分裂症相关的miR-137靶标基因的功能性脑关联进行了表征。

方法

利用来自死后前额叶皮质的RNA测序数据（N = 522），我们鉴定了一个富含miR-137靶标和精神分裂症风险基因的共表达基因集。我们通过在神经母细胞瘤细胞中操纵miR-137表达，在体外验证了该基因集与miR-137的关系。我们将这个基因集转化为共表达预测的多基因评分，并将其与健康志愿者（n = 214；n = 136；n = 2075；n = 1800）的功能磁共振成像激活以及精神分裂症患者（N = 427）的短期治疗反应相关联。

结果

在4652名人类参与者中，我们发现：1）精神分裂症风险基因在一个经生物学验证的、富含miR-137靶标的基因集中共表达；2）前额叶miR-137低表达介导了miR-137靶标风险基因表达的增加；3）预测基因集共表达程度更高的等位基因与3个独立健康队列（n、n、n）在情绪加工过程中与年龄（n）相互作用时更大的前额叶激活相关；4）这些等位基因预测精神分裂症患者在接受抗精神病药物治疗后阴性症状的改善较少。