Targeting aggression in severe mental illness: The predictive role of genetic, epigenetic, and metabolomic markers

- Aggression is a heritable trait overrepresented in severe mental illness (SMI).
- Environmental moderators act on the liability threshold set by genetic factors.
- Several genetic and epigenetic markers have been identified, but still await validation.
- Metabolomics might help identifying specific risk profiles in SMI, particularly in autism.
- Gut microbiota might play a role in modulating the development of aggression.

Human aggression is a complex and widespread social behavior that is overrepresented in individuals affected by severe mental illness (SMI), such as schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). A substantial proportion of the liability threshold for aggressive behavior is determined by genetic factors, and environmental moderators might precipitate the manifestation of this behavioral phenotype through modification of gene expression via the epigenetic machinery. These specific alterations in the genetic and epigenetic make-up of aggressive individuals might determine distinct biochemical signatures detectable through metabolomics. An additional pathophysiological component playing a role in aggressive behavior might be determined by alterations of gut microbiota. Here, we present a selective review of human data on genetic, epigenetic, and metabolomic markers of aggressive behavior in SMI, discussing also the available evidence on the role of microbiome alterations. Clinical implication of these evidences, as well as future perspectives, will be discussed.