1Pharmacogenomics 2014 Mar 15: 423-31
TitleGenetic variation in the GCG and in the GLP1R genes and antipsychotic-induced weight gain.
AbstractGLP-1 plays a key role in glucose metabolism and influences antipsychotic-induced weight gain (AIWG). Our study is the first to investigate the encoding gene, GCG, and the GLP-1 receptor gene, GLP1R, and association with AIWG.
In 216 schizophrenic patients treated with antipsychotics for up to 14 weeks, we investigated four GCG and 33 GLP1R polymorphisms. Statistical analyses were conducted using SPSS, Haploview 4.2, UNPHASED 3.1.4 and the R-package mbmdr.
We observed association of rs13429709 near GCG with AIWG (p(corr) = 0.044) in patients of European ancestry receiving olanzapine or clozapine (n = 87). We also found significant gene-gene interaction between rs13429709 and rs2268639 in GLP1R. Only nonsignificant trends were observed for GLP1R polymorphisms with AIWG.
We found significant association of rs13429709 with AIWG. Although there was no significant finding for GLP1R, the observed trends and interaction suggest this to be an interesting gene for further examination.
SCZ Keywordsschizophrenia, schizophrenic
2Schizophr. Res. 2014 Dec 160: 73-9
TitleGlucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial.
AbstractGlucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.
SCZ Keywordsschizophrenia, schizophrenic