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

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OBJECTIVE: Antipsychotics often induce excessive weight gain. We hypothesized that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain. This hypothesis was tested in a subset of the 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 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 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 included PPARG and PCSK1 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, composes a pathway of increased risk of excessive antipsychotic-induced weight gain. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

OriginalsprogEngelsk
TidsskriftActa Neuropsychiatrica
Vol/bind32
Nummer2
Sider (fra-til)72-83
Antal sider12
ISSN0924-2708
DOI
StatusUdgivet - 2020

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