整合TWAS和GWAS鉴定欧洲样本中酒精依赖遗传的肠道微生物群-免疫相互作用。

IF 2.5 4区医学 Q3 PHARMACOLOGY & PHARMACY

Alcohol Pub Date : 2025-06-02 DOI:10.1016/j.alcohol.2025.05.006

Haohao Xu , Peng Shen , Zhenglin Zhao , Yushuang Xing , Tonghui Yi , Chao Yang , Han Gao , Hongyan Guo , Mingqian Zhao , Shanbo Zhang , Di Jia , Weiming Zhao

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引用次数: 0

摘要

目的：酒精依赖（AD）是一种具有强烈遗传特征的全球性公共卫生问题。本研究的目的是探讨与AD相关的潜在致病基因和机制。方法：本研究采用多组学孟德尔随机化方法鉴定AD的潜在致病基因。具体而言，我们将转录组全关联研究（TWAS）与基于汇总数据的孟德尔随机化（SMR）相结合，以确定与AD相关的候选基因。此外，利用介导孟德尔随机化来研究肠道微生物群在免疫细胞表型与AD之间的关系中的介导作用。结果：通过对欧洲人群的SMR和综合跨组织和单组织TWAS的联合分析，确定了与AD相关的两个易感基因ADH1C和POLI。通过跨生物TWAS发现了一个与AD相关的新基因座rs62307318。使用孟德尔随机化和全现象关联分析进一步验证了这一发现。此外，孟德尔随机化发现Paceibacteria可能是髓系DC - AC和AD之间的中介。结论：本研究鉴定出与AD密切相关的两个基因，并探讨了AD可能的发病机制，为AD的治疗和发病机制提供了新的认识。

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Integrating TWAS and GWAS identifies gut microbiota–immune interactions to alcohol dependence genetics in European sample

Objective

Alcohol dependence (AD) is a global public health concern with strong genetic characteristics. The purpose of this study was to explore the underlying pathogenic genes and mechanisms associated with AD.

Methods

This study employed a multi-omics Mendelian randomization approach to identify potential disease-causing genes for AD. Specifically, we integrated transcriptome-wide association studies (TWAS) with summary-data-based Mendelian randomization (SMR) to pinpoint candidate genes associated with AD. Additionally, mediating Mendelian randomization was utilized to investigate the mediating role of the gut microbiota in the relationship between immune cell phenotypes and AD.

Results

Two susceptibility genes associated with AD, ADH1C and POLI, were identified a joint analysis of SMR and integrated cross-tissue and single tissue TWAS in European population. A new genetic locus associated with AD, rs62307318, was uncovered through cross-organism TWAS. This finding was further validated using Mendelian randomization and Phenome-wide association analysis. Additionally, Mendelian randomization identified Paceibacteria as a possible mediator between Myeloid DC AC and AD.

Conclusion

This study identified two genes closely related to AD and explored the possible pathogenesis of AD, which provides a new insight into the treatment and pathogenesis of AD.

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来源期刊

Alcohol 医学-毒理学

CiteScore

4.60

自引率

4.30%

发文量

审稿时长

15.6 weeks

期刊介绍： Alcohol is an international, peer-reviewed journal that is devoted to publishing multi-disciplinary biomedical research on all aspects of the actions or effects of alcohol on the nervous system or on other organ systems. Emphasis is given to studies into the causes and consequences of alcohol abuse and alcoholism, and biomedical aspects of diagnosis, etiology, treatment or prevention of alcohol-related health effects. Intended for both research scientists and practicing clinicians, the journal publishes original research on the neurobiological, neurobehavioral, and pathophysiological processes associated with alcohol drinking, alcohol abuse, alcohol-seeking behavior, tolerance, dependence, withdrawal, protracted abstinence, and relapse. In addition, the journal reports studies on the effects alcohol on brain mechanisms of neuroplasticity over the life span, biological factors associated with adolescent alcohol abuse, pharmacotherapeutic strategies in the treatment of alcoholism, biological and biochemical markers of alcohol abuse and alcoholism, pathological effects of uncontrolled drinking, biomedical and molecular factors in the effects on liver, immune system, and other organ systems, and biomedical aspects of fetal alcohol spectrum disorder including mechanisms of damage, diagnosis and early detection, treatment, and prevention. Articles are published from all levels of biomedical inquiry, including the following: molecular and cellular studies of alcohol''s actions in vitro and in vivo; animal model studies of genetic, pharmacological, behavioral, developmental or pathophysiological aspects of alcohol; human studies of genetic, behavioral, cognitive, neuroimaging, or pathological aspects of alcohol drinking; clinical studies of diagnosis (including dual diagnosis), treatment, prevention, and epidemiology. The journal will publish 9 issues per year; the accepted abbreviation for Alcohol for bibliographic citation is Alcohol.