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The Capital Region of Denmark - a part of Copenhagen University Hospital
E-pub ahead of print

A new genetic locus for antipsychotic-induced weight gain: A genome-wide study of first-episode psychosis patients using amisulpride (from the OPTiMiSE cohort)

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  • Sophie E Ter Hark
  • Stéphane Jamain
  • Dick Schijven
  • Bochao D Lin
  • Mark K Bakker
  • Anne Boland-Auge
  • Jean-François Deleuze
  • Réjane Troudet
  • Anil K Malhotra
  • Sinan Gülöksüz
  • Christiaan H Vinkers
  • Bjørn H Ebdrup
  • René S Kahn
  • Marion Leboyer
  • Jurjen J Luykx
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BACKGROUND: Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds.

AIMS: We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain.

METHODS: All subjects included for this genome-wide association study (n=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use <2 weeks in the previous year and/or <6 weeks lifetime). Weight gain was defined as the increase in body mass index from before until approximately 1 month after amisulpride treatment.

RESULTS: Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; β=1.05; p=3.66 × 10-08; n=206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 (p=1.0 × 10-03) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain.

CONCLUSION: Our findings suggest the involvement of rs78310016 and possibly 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.

Original languageEnglish
JournalJournal of psychopharmacology
Pages (from-to)269881120907972
ISSN0269-8811
DOIs
Publication statusE-pub ahead of print - 4 Mar 2020

ID: 59515963