The Genetic and Neural Substrates of Externalizing Behavior

ABSTRACT Background To gain more insight in the biological factors that mediate vulnerability to display, co-occurring, externalizing behaviors, we leveraged genome wide association summary statistics (GWAS) on 13 externalizing phenotypes. Methods After data classification based on genetic resemblance, we performed multivariate genome-wide association meta-analyses (GWAMA) and conducted extensive bioinformatic analyses, including genetic correlation assessment with other traits, Mendelian Randomization, and gene-set and gene expression analyses. Results The genetic data could be categorized into a disruptive behavior (DB) and risk-taking behavior (RTB) factor and subsequent GWAMA provided association statistics for DB and RTB (Neff = 523,150 and 1,506,537, respectively) yielding 50 and 257 independent genetic signals. The statistics of DB, much more than RTB, signalled genetic predisposition to adverse cognitive, mental health and personality outcomes. We found evidence for bidirectional causal influences between DB and substance use behaviors. Gene-set analyses implicated contributions of neuronal cell-development (DB/RTB) and synapse formation and transcription (RTB) mechanisms. Gene-brain mapping confirmed involvement of the amygdala and hypothalamus and highlighted other candidate regions (cerebellar dentate, cuneiform nucleus, claustrum, paracentral cortex). At cell-type level, we note enrichment of glutamatergic neurons for DB and RTB. Conclusions This bottom-up data-driven study provides new insights into the genetic signals of externalizing behaviors and indicates that commonalities in genetic architecture contribute to the frequent co-occurrence of different disruptive behaviors and different risk-taking behaviors, respectively. Bioinformatic analyses supported the DB versus RTB categorization and indicated relevant biological mechanisms. Generally similar gene-brain mappings indicate that neuroanatomical differences, if any, escaped the resolution of our methods.