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

Published online by Cambridge University Press:  14 November 2019

Henrik Thyge Corfitsen Open the ORCID record for Henrik Thyge Corfitsen [Opens in a new window] ,
Betina Krantz ,
Agnete Larsen  and
Antonio Drago Open the ORCID record for Antonio Drago [Opens in a new window]
Henrik Thyge Corfitsen*
Affiliation:
Institute for Biomedicin, Aarhus University, Psykiatrisk Forskningsenhed Vest, Herning, Denmark
Betina Krantz
Affiliation:
VIA University College, Holstebro, Denmark
Agnete Larsen
Affiliation:
Institute for Biomedicin, Forskning og uddannelse, Aarhus University, Øst, Denmark
Antonio Drago
Affiliation:
Institute for Biomedicin, Aarhus University, Psykiatrisk Forskningsenhed Vest, Herning, Denmark
*
Author for correspondence: Henrik Thyge Corfitsen, Email: htcorfitsen@gmail.com
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Abstract

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.

Keywords

antipsychotic agentsmetabolic networks and pathwayspharmacogeneticspolymorphismsingle nucleotideweight gain
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 2 , April 2020 , pp. 72 - 83
Copyright
© Scandinavian College of Neuropsychopharmacology 2019

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