A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia

Abstract

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.

Figure 1

CNR1 gene structure, linkage disequilibrium observed and the results of association analysis. (a) Gene structure of CNR1. Alternative splicing is known to occur at CNR1 and five transcripts have been identified (Zhang et al, 2004). The two most common transcripts are shown. The gray filled boxes represent the coding region. (b) Linkage disequilibrium among the 20 tag SNPs tested and their location. Standard color scheme is used (Haploview 4.0). Please refer to the online version of the article for the colors. Bright red represents D′=1 and LOD⩾2; shades of pink/red, D′<1 and LOD⩾2; blue, D′=1 and LOD<2; white, D′<1 and LOD<2. The values in the boxes represent r². A high correlation was observed between rs806378 and rs806380 (r²=0.76); and rs9450902 and rs10485170 (r²=0.84). (c) Summary of results for allelic , genotypic and haplotypic (three marker sliding window) analyses between the SNPs and antipsychotic-induced weight gain. The SNP rs806378 shows both allelic and genotypic association whereas rs9450902 and rs10485170 show only allelic association. The color reproduction of this figure is available on the html full text version of the manuscript.

Figure 2

Electrophoretic mobility shift assay for SNP rs806378. Identification of nuclear proteins binding to the T-allele (Lane 1–4) and C-allele (Lane 5–8). Our genetic studies suggested the T allele (TT+TC) was associated with antipsychotic-induced weight gain. Lane 2 shows binding of the transcription factor ARNT with the T allele.