The Role of Leptin-Melanocortin System Gene Variants in Antipsychotic-Induced Weight Gain

The use of second-generation antipsychotic medications can result in the development of severe side effects such as weight gain and metabolic syndrome. Previous studies have proposed that a genetic component contributes between 40% and 80% to the development of this side effect. However, genetic studies thus far have yielded mixed findings. The genetics of the melanocortin system has not yet been extensively examined in the context of antipsychotic-induced weight gain. Objectives: The first objective was to investigate whether melanocortinergic single nucleotide polymorphisms from genes that were associated with high weight and obesity were also associated with antipsychotic-induced weight gain. The second objective was to determine whether gene-gene interactions better predict the onset of antipsychotic-induced weight gain in psychiatric patients. Hypothesis: It was predicted that the melanocortin-3 receptor, melanocortin-4 receptor, pro-opiomelanocortin, cocaine-amphetamine regulated transcript, and agouti related protein would be associated with antipsychotic-induced weight gain, and that a combination of these genes would provide improved prediction of this phenotype. Results: The melanocortin-3 and melanocortin-4 receptors were associated with antipsychotic-induced weight gain. An additive model did not demonstrate that the combined effect in these genes explains increased variance of the weight gain phenotype. Conclusions: The melanocortin receptor system may have a more substantial role in predicting antipsychotic-induced weight gain, as compared to previously studied gene systems. Though further exploration and functional analyses are required, these findings contribute novel knowledge to the pharmacogenetics of antipsychotic-induced weight gain, and may help to enhance the development of clinical genetic tests to guide medication decision-making in the future.