The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction and related behavioral traits

Ester Antón-Galindo; Judit Cabana-Domínguez; Bàrbara Torrico; Roser Corominas; Bru Cormand; Noèlia Fernàndez-Castillo

doi:10.3389/fpsyt.2023.1293663

The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction and related behavioral traits

Front Psychiatry. 2023 Oct 23:14:1293663. doi: 10.3389/fpsyt.2023.1293663. eCollection 2023.

Authors

Ester Antón-Galindo^{1

2

3

4}, Judit Cabana-Domínguez^{5

6

7}, Bàrbara Torrico¹, Roser Corominas^{1

2

3

4}, Bru Cormand^{1

2

3

4}, Noèlia Fernàndez-Castillo^{1

2

3

4}

Affiliations

¹ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
² Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
³ Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
⁴ Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
⁵ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁶ Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁷ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.

Abstract

Introduction: 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.

Methods: 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.

Results: 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: ADH1C, ARNTL, CHRNA3, HPRT1, HTR1B and DRD2. 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.

Discussion: 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.

Keywords: GWAS; SUD; addiction; aggression; dopamine; genetics; pleiotropy; serotonin.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Major financial support for this research was received by NF-C from the Spanish “Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas” (PNSD-2020I042), “Ministerio de Ciencia, Innovación y Universidades” (PID2021-1277760B-I100), and “Generalitat de Catalunya/AGAUR” (2021-SGR-01093). BC received funding from ICREA Academia 2021, the European Union H2020 Program (H2020/2014-2020) under grant agreement 728018 (Eat2beNICE) and “Fundació La Marató de TV3” (202218-31). EA-G was supported by the PNSD-2020I042, Eat2beNICE and a Margarita Salas postdoctoral grant. RC is a recipient of a Ramón y Cajal contract (RYC-2017-21636). JC-D was supported by the CIBERSAM and a Ramón y Cajal postdoctoral grant (RYC2021-031324-I).