Molecular pathway analysis associates alterations in obesity-related genes and antipsychotic-induced weight gain

OBJECTIVE: Antipsychotics often induce excessive weight gain. We hypothesised that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain (AIWG). This hypothesis was tested in a subset of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data set.

METHODS: The CATIE trial compared effects and side effects of five different antipsychotics through an 18-month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight gain. Cytoscape and GeneMANIA were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 single-nucleotide polymorphisms (SNPs) were available from 765 (556 males) individuals. Enrichment test was conducted through ReactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p ≤ 0.05). In addition, a standard genome-wide association study (GWAS) analysis was performed.

RESULT: GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p < 0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes including PPARG and PCSK1 were not previously related to treatment-induced weight gain.

CONCLUSIONS: The molecular pathway composed from high-risk obesity genes was shown to overlap with genetics of patients who gained >7% weight gain during the CATIE trial. This suggests that genes related to obesity compose a pathway of increased risk of excessive AIWG. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.