Inhibitory neuron links the causal relationship from air pollution to psychiatric disorders: a large multi-omics analysis

IF 8.6 2区 计算机科学 Q1 COMPUTER SCIENCE, THEORY & METHODS
Xisong Liang, Jie Wen, Chunrun Qu, Nan Zhang, Ziyu Dai, Hao Zhang, Peng Luo, Ming Meng, Zhixiong Liu, Fan Fan, Quan Cheng
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Abstract

Psychiatric disorders are severe health challenges that exert a heavy public burden. Air pollution has been widely reported as related to psychiatric disorder risk, but their casual association and pathological mechanism remained unclear. Herein, we systematically investigated the large genome-wide association studies (6 cohorts with 1,357,645 samples), single-cell RNA (26 samples with 157,488 cells), and bulk-RNAseq (1595 samples) datasets to reveal the genetic causality and biological link between four air pollutants and nine psychiatric disorders. As a result, we identified ten positive genetic correlations between air pollution and psychiatric disorders. Besides, PM2.5 and NO2 presented significant causal effects on schizophrenia risk which was robust with adjustment of potential confounders. Besides, transcriptome-wide association studies identified the shared genes between PM2.5/NO2 and schizophrenia. We then discovered a schizophrenia-derived inhibitory neuron subtype with highly expressed shared genes and abnormal synaptic and metabolic pathways by scRNA analyses and confirmed their abnormal level and correlations with the shared genes in schizophrenia patients in a large RNA-seq cohort. Comprehensively, we discovered robust genetic causality between PM2.5, NO2, and schizophrenia and identified an abnormal inhibitory neuron subtype that links schizophrenia pathology and PM2.5/NO2 exposure. These discoveries highlight the schizophrenia risk under air pollutants exposure and provide novel mechanical insights into schizophrenia pathology, contributing to pollutant-related schizophrenia risk control and therapeutic strategies development.

Graphical Abstract

Abstract Image

抑制性神经元将空气污染与精神疾病的因果关系联系起来:大型多组学分析
精神疾病是严峻的健康挑战,给公众带来沉重负担。空气污染与精神疾病风险的关系已被广泛报道,但其偶然关联和病理机制仍不清楚。在此,我们系统地研究了大型全基因组关联研究(6 个队列,1,357,645 个样本)、单细胞 RNA(26 个样本,157,488 个细胞)和批量 RNAseq(1595 个样本)数据集,以揭示四种空气污染物与九种精神疾病之间的遗传因果关系和生物学联系。结果,我们发现了空气污染与精神疾病之间的十种正遗传相关性。此外,PM2.5 和二氧化氮对精神分裂症风险具有显著的因果效应,在调整了潜在的混杂因素后,这种效应是稳健的。此外,全转录组关联研究发现了PM2.5/二氧化氮与精神分裂症之间的共有基因。然后,我们通过scRNA分析发现了精神分裂症衍生的抑制性神经元亚型,该亚型具有高表达的共享基因以及异常的突触和代谢通路,并在一个大型RNA-seq队列中证实了精神分裂症患者的异常水平及其与共享基因的相关性。总之,我们发现了PM2.5、二氧化氮和精神分裂症之间的强大遗传因果关系,并确定了一种异常抑制性神经元亚型,它将精神分裂症病理和PM2.5/二氧化氮暴露联系在一起。这些发现凸显了空气污染物暴露下的精神分裂症风险,并为精神分裂症病理提供了新的力学见解,有助于与污染物相关的精神分裂症风险控制和治疗策略的开发。图文摘要
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来源期刊
Journal of Big Data
Journal of Big Data Computer Science-Information Systems
CiteScore
17.80
自引率
3.70%
发文量
105
审稿时长
13 weeks
期刊介绍: The Journal of Big Data publishes high-quality, scholarly research papers, methodologies, and case studies covering a broad spectrum of topics, from big data analytics to data-intensive computing and all applications of big data research. It addresses challenges facing big data today and in the future, including data capture and storage, search, sharing, analytics, technologies, visualization, architectures, data mining, machine learning, cloud computing, distributed systems, and scalable storage. The journal serves as a seminal source of innovative material for academic researchers and practitioners alike.
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