Metabotropic glutamate receptor 3 is associated with heroin dependence but not depression or schizophrenia in a Chinese population

Abstract

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.

Figure 1. Gene structure of human GRM3 and the relative positions of the 17 SNPs used in our study.

The schematic diagram of GRM3 gene is based on NCBI reference sequences NM 00084.2 and marks exons by the black bars orderly nominated A–F. The bands with serial number A–F below gene chart show the start and end position of corresponding exon in their left and right terminals. The black parts of these bands represent untranslated sequence, and the gray parts of these bands represent coding DNA sequence (CDS).

Figure 2. Kaplan–Meier survival curves representing probability that individuals have not experienced dependence over the period of time following first opioid use.

Total addicts stratified by genotype of rs274618.

Figure 3. Linkage disequilibrium (LD) plot of 17 GRM3 SNPs in healthy controls. In figure A, the r² × 100 value corresponding to each SNP pair is shown in the square; black squares indicate r² = 1, i.e., complete LD; white squares indicate r² = 0; shaded grey squares indicate 0< r²<1.

In figure B, D′ × 100 value corresponding to each SNP pair is shown in the square; white squares indicate D′ <1 and LOD <2; blue squares indicate D′ = 1 and LOD <2; shaded red squares indicate D′ <1 and LOD ≥2; bright red squares indicate D′ = 1 and LOD ≥2.