Increased burden of rare protein-truncating variants in constrained, brain-specific and synaptic genes in extremely impulsively violent males with antisocial personality disorder.

The genetic correlates of extreme impulsive violence are poorly understood, and there have been few studies that have characterized a large group of affected individuals both clinically and genetically. We performed whole exome sequencing (WES) in 290 males with the life-course-persistent, extremely impulsively violent form of antisocial personality disorder (APD) and analyzed the spectrum of rare protein-truncating variants (rPTVs). Comparisons were made with 314 male controls and publicly available genotype data. Functional annotation tools were used for biological interpretation. Participants were significantly more likely to harbor rPTVs in genes that are intolerant to loss-of-function variants (odds ratio [OR] 2.06; p < 0.001), specifically expressed in brain (OR 2.80; p = 0.036) and enriched for those involved in neurotransmitter transport and synaptic processes. In 60 individuals (20%), we identified rPTVs that we classified as clinically relevant based on their clinical associations, biological function and gene expression patterns. Of these, 37 individuals harbored rPTVs in 23 genes that are associated with a monogenic neurological disorder, and 23 individuals harbored rPTVs in 20 genes reportedly intolerant to loss-of-function variants. The analysis presents evidence in support of a model where presence of either one or several private, functionally relevant mutations contribute significantly to individual risk of life-course-persistent APD and reveals multiple individuals who could be affected by clinically unrecognized neuropsychiatric Mendelian disease. Thus, Mendelian diseases and increased rPTV burden may represent important factors for the development of extremely impulsive violent life-course-persistent forms of APD irrespective of their clinical presentation.

The effect of microbiome composition on impulsive and violent behavior: A systematic review.

The impact of the microbiome on brain function and behavior has recently become an important research topic. We searched for a link between the gut microbiome and impulsive and violent behavior. We focused on critical factors influencing the microbiome establishment that may affect human health later in life, i.e., delivery mode, early-life feeding, and early antibiotic exposure. We searched PubMed, Web of Science, and the Cochrane Library. We included original human studies examining adults and children with impulsive and/or violent behavior that assessed the gut microbiota composition of participants, delivery mode, infant feeding mode, or early antibiotic exposure. Bibliographic searches yielded 429 articles, and 21 met the eligibility criteria. Two studies reported data on patients with schizophrenia with violent behavior, while 19 studies reported data on patients with attention-deficit hyperactivity disorder (ADHD). The results showed several bacterial taxa associated with ADHD symptomatology and with violent behavior in patients with schizophrenia. No association was found between delivery mode and impulsive behavior, nor did any articles relate infant feeding mode to violent human behavior. Those studies investigating early antibiotic exposure yielded ambiguous results. The heterogeneity of the data and the different methodologies of the included studies limited the external validity of the results. We found few studies that addressed the possible microbiome involvement in the pathophysiology of impulsive and violent behavior in humans. Our review revealed a gap in knowledge regarding links between the gut microbiome and these extreme behavioral patterns.