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全面探索多巴胺能和血清素能通路对精神疾病的遗传贡献。

Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders.

作者信息

Cabana-Domínguez Judit, Torrico Bàrbara, Reif Andreas, Fernàndez-Castillo Noèlia, Cormand Bru

机构信息

Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain.

出版信息

Transl Psychiatry. 2022 Jan 10;12(1):11. doi: 10.1038/s41398-021-01771-3.

Abstract

Psychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to play an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), anorexia nervosa (ANO), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette's syndrome (TS)) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium that include more than 160,000 cases and 275,000 controls. To do so, we elaborated four different gene sets: two 'wide' selections for dopamine (DA) and for serotonin (SERT) using the Gene Ontology and KEGG pathways tools, and two'core' selections for the same systems, manually curated. At the gene level, we found 67 genes from the DA and/or SERT gene sets significantly associated with one of the studied disorders, and 12 of them were associated with two different disorders. Gene-set analysis revealed significant associations for ADHD and ASD with the wide DA gene set, for BIP with the wide SERT gene set, and for MD with the core SERT set. Interestingly, interrogation of a cross-disorder GWAS meta-analysis of the eight psychiatric conditions displayed association with the wide DA gene set. To our knowledge, this is the first systematic examination of genes encoding proteins essential to the function of these two neurotransmitter systems in these disorders. Our results support a pleiotropic contribution of the dopaminergic and serotonergic systems in several psychiatric conditions.

摘要

精神疾病极为普遍,且在临床和遗传方面存在相当大的重叠。多巴胺能和血清素能神经传递在许多精神疾病中发挥着重要作用。在此,我们旨在利用精神疾病基因组学联盟进行的公开全基因组关联研究(GWAS)分析,评估这些系统对八种精神疾病(注意力缺陷多动障碍(ADHD)、神经性厌食症(ANO)、自闭症谱系障碍(ASD)、双相情感障碍(BIP)、重度抑郁症(MD)、强迫症(OCD)、精神分裂症(SCZ)和图雷特综合征(TS))的遗传贡献,该分析涵盖了超过160,000例病例和275,000名对照。为此,我们精心构建了四个不同的基因集:利用基因本体论和KEGG通路工具对多巴胺(DA)和血清素(SERT)进行两种“宽泛”选择,以及对相同系统进行两种手动筛选的“核心”选择。在基因水平上,我们发现来自DA和/或SERT基因集的67个基因与所研究的疾病之一显著相关,其中12个与两种不同疾病相关。基因集分析显示,宽泛的DA基因集与ADHD和ASD显著相关,宽泛的SERT基因集与BIP相关,核心SERT基因集与MD相关。有趣的是,对这八种精神疾病的跨疾病GWAS荟萃分析显示与宽泛的DA基因集有关联。据我们所知,这是首次对编码这两种神经递质系统功能所必需蛋白质的基因在这些疾病中的系统研究。我们的结果支持多巴胺能和血清素能系统在几种精神疾病中的多效性贡献。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bd7/8748838/55a7897be3e8/41398_2021_1771_Fig1_HTML.jpg

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