GXE INTERACTION EFFECTS OF HCRTR2 SINGLE NUCLEOTIDE POLYMORPHISM AND ADVERSE CHILDHOOD EXPERIENCES ON METHAMPHETAMINE USE DISORDER

Abstract Background Methamphetamine (METH) use disorder (MUD) is a major global health concern. The hypothalamic orexin system regulates stress response and addictive behaviors. The genetic variation in the hypocretin receptor 2 (HCRTR2), rs2653349, is associated with substance dependence. We explored the gene- environment (GxE) interaction of SNP rs2653349 and adverse childhood experiences (ACEs) in relation to MUD susceptibility. We explored the gene-environment (GxE) interaction involving SNP rs2653349 and early-life stress factors, adverse childhood experiences (ACEs), in relation to MUD susceptibility. Methods Four hundred and one individuals with MUD and 348 healthy controls completed a self-report questionnaire evaluating ACEs, encompassing childhood abuse and household dysfunction categories, and were genotyped for SNP rs2653349. METH use variables were collected using the Diagnostic Interview for Genetic Studies. We used regression analyses to assess the GxE effect on MUD risk. Results The MUD group had a comparable genotypic distribution for rs2653349 to the control group, albeit with a higher prevalence and number of types of ACEs, which was linked to an increased MUD risk (p <0.05). No significant genetic impact of rs2653349 on MUD risk was found. However, we observed a GxE interaction effect between the minor allele of rs2653349 and the number of childhood abuse or household dysfunction types, correlating with a reduced MUD risk (OR = -0.71, p = 0.04, adjusted p = 0.08 and OR = -0.59, p = 0.045, adjusted p = 0.09, respectively). Conclusion HCRTR2 SNP rs2653349 has no significant impact on MUD risk, but ACEs might increase this risk. GxE results suggest that rs2653349 could offer protection against developing MUD in individuals experiencing multiple types of ACEs.