The influence of CHRNA5 and D398N missense variation on social and emotional behaviors in rodents and humans

Social behavior alterations, notably aggressivity-related behavioral states (ARBS), and substance use disorders (SUDs) show consistent associations. In psychopathology, ARBS and SUDs cluster together as externalizing disorders, which show evidence for shared genetic liability and are associated with emotional dysregulation. Human studies have identified a single nucleotide polymorphism (rs16969968) of CHRNA5 encoding the α5 subunit of nicotinic acetylcholine receptors (nAChRs) (hereafter called α5SNP) in association with nicotine dependence. The influence of α5 containing nAChRs (α5*nAChRs) and α5SNP on social behavior, ARBS and emotional regulation, promising endophenotypes for SUDs, remain to be characterized. We investigated dyadic and higher-level group social interactions, notably in response to nicotine, in rodents either knockout for Chrna5 or α5SNP carriers. We further conducted a genetic association study, in a student population, between α5SNP and a comprehensive set of ARBS-related psychometric items. Finally, we leveraged publicly-available findings from genome wise association studies (GWASs) to further characterize the link between α5SNP and ARBS. We show that α5*nAChRs modulate agonistic and dominance-like behaviors and nicotine's effects on these behaviors, and that α5SNP is associated with social alterations, in rodents. In students, α5SNP was associated with emotional dysregulation. This was partially supported by GWASs of ARBS-related traits, where associations were of small effect magnitude. The present results, by suggesting a novel role of α5*nAChRs and of the α5SNP in social -including ARBS- in rodents, and emotional dysregulation in humans, may serve as a basis to develop ligands targeting these receptors for treating ARBS, notably in the context of SUDs.