The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction, aggression and related behavioural traits

Co-occurrence of substance use disorders (SUD) and aggressive behaviour in the same individual has been frequently described. As dopamine (DA) and serotonin (5-HT) are key neurotransmitters for both phenotypes, we explored the genetic contribution of these pathways to SUD, aggressive behaviour and related behavioural traits. Here, 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 (TWAS) in 11 genome-wide association studies (GWAS) datasets on SUD (alcohol, cocaine, cannabis, opioids and a multivariate analysis of three drugs of abuse), aggressive behaviour (disruptive behaviour and antisocial behaviour) and related behaviours (irritability, neuroticism, risk taking and anxiety). 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 behaviour. Among them, six genes had a pleiotropic effect, being associated with at least three phenotypes: ADH1C, ARNTL, CHRNA3, HPRT1, HTR1B and DRD2, the latter with five. Additionally, we found nominal associations between the DA gene sets and antisocial behaviour, opioid use disorder, SUD, irritability and neuroticism, and between the 5-HT-core gene set and neuroticism. Gene expression correlates in brain were also found for 19 genes, highlighting the association for CHRNA3 and CELSR3 with OUD, SUD and irritability and CELSR3 also with neuroticism. Our study shows a pleiotropic contribution of dopaminergic and serotonergic genes to addiction, aggression and related behaviours, highlighting a special role for DA genes, which could explain, in part, the co-occurrence of these phenotypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by several institutions listed in the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: N/A I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.