Aggression and substance use disorders (SUDs) show consistent associations, although their causal link remains to be understood. Human genetic studies have identified an association between a single nucleotide polymorphism (rs16969968) of the CHRNA5 gene encoding the α5 subunit of the nicotinic acetylcholine receptors (nAChRs) (α5SNP) and higher scores of nicotine dependence. We and others have shown that the α5SNP is associated with a loss of function of α5 containing nAChRs (α5*nAChRs) and strongly modulates addiction-like behaviors in response not only to nicotine but also to alcohol and cocaine. nAChRs are crucial regulators of mood, yet the influence of α5*nAChRs and of the α5SNP on aggressiveness and its modulation by nicotine, which represent promising endophenotypes for SUDs, remain to be characterized. Here we show enhanced agonistic and dominant-like behaviors in rodent models either knockout for chrna5 or constitutive carriers of the α5SNP. We investigated both short-term dyadic interactions, notably in response to nicotine, and higher-level and long-term group interactions using the Live Mouse Tracker for comprehensive behavioral analysis. Finally, we conducted a genetic association study in a large population of young adults assessed for a comprehensive set of psychometric items, further categorized into key psycho-emotional dimensions by exploratory factor analysis. In this population assessed before the development of chronic/severe SUDs, we show that the α5SNP is significantly associated with aggression after adjustment for age, gender and emotional dysregulation. Ligands acting at α5*nAChRs may represent a novel pharmacological approach for treating aggressive behavior notably in the context of SUD.