Genetic variation of GRIA3 gene is associated with vulnerability to methamphetamine dependence and its associated psychosis

Methamphetamine (METH) is an addictive psychostimulant drug commonly leading to schizophrenia-like psychotic symptoms. Disturbances in glutamatergic neurotransmission have been proposed as neurobiological mechanisms and the α-amino-3 hydroxy-5 methyl-4 isoxazole propionic acid (AMPA) glutamate receptor has been implicated in these processes. Moreover, genetic variants in GRIAs, genes encoding AMPA receptor subunits, have been observed in association with both drug dependence and psychosis. We hypothesized that variation of GRIA genes may be associated with METH dependence and METH-induced psychosis. Genotyping of GRIA1 rs1428920, GRIA2 rs3813296, GRIA3 rs3761554, rs502434 and rs989638 was performed in 102 male Thai controls and 100 METH-dependent subjects (53 with METH-dependent psychosis). We observed no evidence of association with METH dependence and METH-dependent psychosis in the GRIA1 and GRIA2 polymorphisms, nor with single polymorphisms rs3761554 and rs989638 in GRIA3. An association of GRIA3 rs502434 was identified with both METH dependence and METH-dependent psychosis, although this did not withstand correction for multiple testing. Combining the analysis of this site with the previously-demonstrated association with BDNF rs6265 resulted in a highly significant effect. These preliminary findings indicate that genetic variability in GRIA3 may interact with a functional BDNF polymorphism to provide a strong risk factor for the development of METH dependence in the Thai population.