The rs274622 SNP, or other functional SNPs within GRM3 haplotype block 1 and in strong LD with the aforementioned risk SNPs for HD, may decrease the ability of mGLuR3 to regulate the glutamate balance in the PFC-NAc circuit during chronic heroin use by affecting receptor expression regulation or function and up-regulate the susceptibility to uncontrolled and compulsive heroin use. The gene discussed is GRM3; the disease is Huntington disease.