Deciphering the genetic underpinnings of neuroticism: A Mendelian randomization study of druggable gene targets.

IF 4.9 2区医学 Q1 CLINICAL NEUROLOGY Journal of affective disorders Pub Date : 2024-11-02 DOI:10.1016/j.jad.2024.11.002

Yanggang Hong, Yi Wang, Wanyi Shu

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Abstract

Background: Neuroticism, known for its association with a greater risk of psychiatric conditions such as depression and anxiety, is a critical focus of research.

Methods: Cis-expression quantitative trait loci (eQTLs) from 31,684 whole blood samples provided by the eQTLGen Consortium, alongside data from a large neuroticism cohort, were analyzed to identify genes causally linked to neuroticism. To further explore the influence of gene expression changes on neuroticism, colocalization analysis was conducted. Identified drug targets were assessed for potential side effects using a phenome-wide association study (PheWAS). Additionally, we utilized multiple databases to explore the interactions between drugs and genes for drug prediction and assess the current medications for drug repurposing.

Results: The analysis involved a total of 4473 druggable genes, with two-sample Mendelian randomization (MR) identifying 186 genes that are causally linked to neuroticism. Colocalization analysis highlighted 11 genes (TLR4, MMRN1, EP300, BRAF, ORM1, ACVR1B, LRRC17, NOS2, ADAMTS6, GPX1, and VCL) with a posterior probability of colocalization (PPH4) >0.8. PheWAS revealed that drugs targeting BRAF, LRRC17, ADAMTS6, and GPX1 were also associated with other traits. Notably, six of these genes (TLR4, MMRN1, BRAF, ACVR1B, NOS2, and GPX1) are already being explored for drug development in psychiatric and other diseases.

Conclusion: This study pinpointed six genes as promising therapeutic targets for neuroticism. The repurposing and development of drugs targeting these genes hold potential for managing neuroticism and associated psychiatric disorders.

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解密神经质的遗传基础：可药用基因靶点的孟德尔随机化研究。

背景：神经质与抑郁和焦虑等精神疾病的高风险有关，是研究的一个重要焦点：方法：分析了由 eQTLGen 联合会提供的 31,684 份全血样本中的顺式表达定量性状位点（eQTLs）以及来自大型神经质队列的数据，以确定与神经质有因果关系的基因。为了进一步探索基因表达变化对神经质的影响，还进行了共定位分析。利用全表型关联研究（PheWAS）评估了已确定的药物靶点的潜在副作用。此外，我们还利用多个数据库探索药物与基因之间的相互作用，以进行药物预测，并评估目前的药物再利用：分析共涉及 4473 个可用药基因，通过双样本孟德尔随机化（MR）确定了 186 个与神经质有因果关系的基因。共定位分析显示，11个基因（TLR4、MMRN1、EP300、BRAF、ORM1、ACVR1B、LRRC17、NOS2、ADAMTS6、GPX1和VCL）的共定位后验概率（PPH4）大于0.8。PheWAS显示，针对BRAF、LRRC17、ADAMTS6和GPX1的药物也与其他性状相关。值得注意的是，其中六个基因（TLR4、MMRN1、BRAF、ACVR1B、NOS2 和 GPX1）已被用于精神疾病和其他疾病的药物开发：结论：本研究确定了六个基因作为神经质的治疗靶点。结论：本研究将六个基因确定为治疗神经质的有希望的靶点，针对这些基因的药物的再利用和开发为治疗神经质和相关精神疾病提供了可能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of affective disorders 医学-精神病学

CiteScore

10.90

自引率

6.10%

发文量

1319

审稿时长

9.3 weeks

期刊介绍： The Journal of Affective Disorders publishes papers concerned with affective disorders in the widest sense: depression, mania, mood spectrum, emotions and personality, anxiety and stress. It is interdisciplinary and aims to bring together different approaches for a diverse readership. Top quality papers will be accepted dealing with any aspect of affective disorders, including neuroimaging, cognitive neurosciences, genetics, molecular biology, experimental and clinical neurosciences, pharmacology, neuroimmunoendocrinology, intervention and treatment trials.