• Aggression;
  • anger;
  • assault;
  • CRHR1;
  • depression;
  • gene;
  • HPA axis;
  • SNP;
  • stress;
  • suicidality

Risk factors for suicidal behaviors are partly heritable, including genetic variants that drive diathesis–stress in addition to, or by interaction with, exposure to certain stressful life events (SLEs). Hypothalamic–pituitary–adrenal (HPA) axis regulatory genes are candidates for association with suicide as well as its endophenotypes. Using a family-based design of offspring who attempted suicide (SA) and both parents, we investigated gene–environment interactions (G×Es) of SLE exposures with single nucleotide polymorphisms (SNPs) in corticotropin-releasing hormone receptor-1 (CRHR1), a major HPA axis regulatory gene. We observed a novel G×E among predominantly female SA between 5′-SNP rs7209436 and childhood/adolescence physical assault or attack (PA), as well as a second novel and male-specific G×E between 3′-SNP rs16940665 and adulthood PA exposure. A third male-specific G×E previously reported by us among depressed SA, between SNP rs4792887 and cumulative SLEs, was also further confirmed. The two novel G×Es presented here shared the SA characteristic of aggression, while showing differences on other aspects of SA heterogeneity. We conclude that different SA subjects were observed to differentially associate with two novel G×Es involving exposures to PA with different life timing and SNPs located in opposite ends of CRHR1. Concerning sex differences, we observed three subsets of distinct male SA that associated with each of the three observed G×Es, whereas female SAs were affected by only one of the G×Es. These results are consistent with a diathesis–stress model of suicidal behavior and may help to explain SA heterogeneity.