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Metabotropic glutamate receptor subtype 3 (mGluR3, encoded by  GRM3 ) plays important roles in the pathophysiology of schizophrenia, depression, and drug dependence.  GRM3  polymorphisms were reported to be associated with prefrontal activity, cognitive shifting, and memory capability in healthy subjects, as well as susceptibility to schizophrenia and depression. The goal of this study was to replicate the association of  GRM3  with schizophrenia and depression and to explore  GRM3’s  potential association with heroin dependence (HD) in a Chinese population. Seventeen SNPs throughout the  GRM3  gene were genotyped using MALDI-TOF within the MassARRAY system, and the allele and genotype distributions were compared between 619 healthy controls and 433 patients with schizophrenia, 409 patients with major depression, and 584 unrelated addicts. We found that  GRM3  polymorphisms modulate the susceptibility to HD but do not significantly influence the risk for schizophrenia or depression. An increased risk of HD was significantly associated with the minor alleles of two  GRM3  SNPs, including the T allele of rs274618 (Odds ratio (OR) = 1.631, 95% confidence interval (95%CI): 1.317–2.005), the T allele of rs274622 (OR = 1.652, 95% CI: 1.336–2.036), compared with the major alleles. The addicts carrying the minor allele of rs274618 or rs274622 had a shortened duration for transition from first use to dependence (DTFUD) in comparison to homozygote for major allele ( P <0.0001 for each SNP using log rank test). Additionally, a 6-SNP haplotype within 5′ region of the  GRM3  including the minor alleles of the two aforementioned SNPs was significantly associated with an increased risk of HD ( P  = 0.00001, OR = 1.668, 95% CI: 1.335–2.084). Our data indicated that  GRM3  polymorphisms do not contribute to genetic susceptibility to schizophrenia and depression, but they confer an increased risk of HD in a Chinese population.

Metabotropic Glutamate Receptor 3 Is Associated with Heroin Dependence but Not Depression or Schizophrenia in a Chinese Population