Ramsey Timothy L, Brennan Mark D
SureGene, LLC, 600 Envoy Circle, Louisville, KY 40299, USA.
SureGene, LLC, 600 Envoy Circle, Louisville, KY 40299, USA.
Schizophr Res. 2014 Dec;160(1-3):73-9. doi: 10.1016/j.schres.2014.09.038. Epub 2014 Oct 18.
Glucagon-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.
胰高血糖素样肽1受体（GLP1R）信号通路在动物模型中已显示出具有抗精神病特性，并影响人体中葡萄糖依赖性胰岛素释放、饱腹感、记忆和学习。先前的研究表明，两个编码突变（rs6923761和rs1042044）与胰岛素释放和皮质醇水平的改变有关。我们在白种人中鉴定出四种常见的单倍型，即单倍型1至单倍型4，跨越外显子4至7并包含这两个编码变体。我们分析了来自干预有效性临床抗精神病试验的白种人受试者对抗精神病药物的反应，该反应定义为18个月时阳性和阴性症状量表总分（dPANSS）的预测变化，这些受试者分别接受了奥氮平（n = 139）、奋乃静（n = 78）、喹硫平（n = 14）、利培酮（n = 143）和齐拉西酮（n = 90）治疗。单倍型趋势回归分析显示，奥氮平（最佳p = 0.002）、奋乃静（最佳p = 0.01）、喹硫平（最佳p = 0.008）、利培酮（最佳p = 0.02）和齐拉西酮（最佳p = 0.007）的dPANSS存在显著关联。我们还评估了两种最常见单倍型的遗传模型。单倍型1（独特地包含rs1042044 [Leu(260)] 等位基因）与对奥氮平（p = 0.002）和利培酮（p = 0.006）的更好反应相关，而与对奋乃静（p = 0.03）和齐拉西酮（p = 0.003）的更差反应相关，隐性遗传模型拟合最佳。单倍型2（独特地包含rs6923761 [Ser(168)] 等位基因）与对奋乃静的更好反应（p = 0.001）和对奥氮平的更差反应（p = 0.02）相关，显性遗传模型拟合最佳。然而，GLP1R单倍型与抗精神病药物引起的体重增加无关。这些结果将GLP1R中的功能性基因变异与抗精神病反应联系起来。
