Antón-Galindo Ester, Cabana-Domínguez Judit, Torrico Bàrbara, Corominas Roser, Cormand Bru, Fernàndez-Castillo Noèlia
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Front Psychiatry. 2023 Oct 23;14:1293663. doi: 10.3389/fpsyt.2023.1293663. eCollection 2023.
Co-occurrence of substance use disorders (SUD) and other behavioral conditions, such as stress-related, aggressive or risk-taking behaviors, in the same individual has been frequently described. As dopamine (DA) and serotonin (5-HT) have been previously identified as key neurotransmitters for some of these phenotypes, we explored the genetic contribution of these pathways to SUD and these comorbid phenotypes in order to better understand the genetic relationship between them.
We tested the association of 275 dopaminergic genes and 176 serotonergic genes with these phenotypes by performing gene-based, gene-set and transcriptome-wide association studies in 11 genome-wide association studies (GWAS) datasets on SUD and related behaviors.
At the gene-wide level, 68 DA and 27 5-HT genes were found to be associated with at least one GWAS on SUD or related behavior. Among them, six genes had a pleiotropic effect, being associated with at least three phenotypes: , , , and . Additionally, we found nominal associations between the DA gene sets and SUD, opioid use disorder, antisocial behavior, irritability and neuroticism, and between the 5-HT-core gene set and neuroticism. Predicted gene expression correlates in brain were also found for 19 DA or 5-HT genes.
Our study shows a pleiotropic contribution of dopaminergic and serotonergic genes to addiction and related behaviors such as anxiety, irritability, neuroticism and risk-taking behavior, highlighting a role for DA genes, which could explain, in part, the co-occurrence of these phenotypes.
物质使用障碍（SUD）与其他行为状况，如与压力相关的、攻击性或冒险行为，在同一个体中同时出现的情况已被频繁描述。由于多巴胺（DA）和血清素（5-HT）先前已被确定为其中一些表型的关键神经递质，我们探索了这些通路对SUD和这些共病表型的遗传贡献，以便更好地理解它们之间的遗传关系。
我们通过在11个关于SUD和相关行为的全基因组关联研究（GWAS）数据集中进行基于基因、基因集和转录组范围的关联研究，测试了275个多巴胺能基因和176个血清素能基因与这些表型的关联。
在全基因水平上，发现68个DA基因和27个5-HT基因与至少一项关于SUD或相关行为的GWAS相关。其中，六个基因具有多效性，与至少三种表型相关： 、 、 、 和 。此外，我们发现DA基因集与SUD、阿片类物质使用障碍、反社会行为、易怒和神经质之间存在名义上的关联，以及5-HT核心基因集与神经质之间存在关联。还发现19个DA或5-HT基因在大脑中的预测基因表达存在相关性。
我们的研究表明，多巴胺能和血清素能基因对成瘾及相关行为，如焦虑、易怒、神经质和冒险行为具有多效性贡献，突出了DA基因的作用，这在一定程度上可以解释这些表型的同时出现。
