A new genetic locus for antipsychotic-induced weight gain: A genome-wide study of first-episode psychosis patients using amisulpride (from the OPTiMiSE cohort). (May 2020)

• Record Type: Journal Article
• Authors: ter Hark, Sophie E; Jamain, Stéphane; Schijven, Dick; Lin, Bochao D; Bakker, Mark K; Boland-Auge, Anne; Deleuze, Jean-François; Troudet, Réjane; Malhotra, Anil K; Gülöksüz, Sinan; Vinkers, Christiaan H; Ebdrup, Bjørn H; Kahn, René S; Leboyer, Marion; Luykx, Jurjen J
• Is Part Of: Journal of psychopharmacology. Volume 34:Number 5(2020)
• Page Start: 524
• Page End: 531
• Publication Date: 2020-05
• Subjects: Pharmacogenetics -- antipsychotics -- body mass index -- amisulpride-induced weight gain -- schizophrenia -- GWAS; Psychopharmacology -- Periodicals; 615.78
• DOI: 10.1177/0269881120907972
• Languages: English
• ISSNs: 0269-8811

Abstract

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.