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

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 antipsychoticinduced 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.

Clinical Utility and Implementation of Pharmacogenomics for the Personalisation of Antipsychotic Treatments

“…One of the most robust pharmacogenetic findings to date is the association of genetic variants in the melanocortin 4 receptor ( MC4R ) with antipsychotic-induced WG, an association that has been confirmed in GWAS and candidate-gene studies (see Table 1 ). Several novel associations with antipsychotic-induced WG have been reported in subsequent genomic studies but have not yet been replicated and require further study [ 57 , 58 , 59 ]. Two GWAS studies have confirmed the previously reported association between genetic variants in the HLA complex and clozapine-induced agranulocytosis [ 46 , 47 ].…”

Polygenic risk scores enhance prediction of body mass index increase in individuals with a first episode of psychosis

“…However, substantial differences in susceptibility between individuals under AP treatment suggest that weight gain may be partially explained by a mixture of environmental effects and genetic background [18][19][20]. In support of this view, the heritability of weight gain in monozygotic twins with SCZ has been estimated to be 0.6-0.8 [21] and a few genetic loci have been associated with AP-induced weight gain by genome-wide association studies (GWAS) [22,23]. Moreover, given its strong polygenic component, SCZ shows extensive genetic overlap with other mental disorders [24,25], and also with other nonpsychiatric traits [26][27][28].…”

Identification of four novel loci associated with psychotropic drug-induced weight gain in a Swiss psychiatric longitudinal study: A GWAS analysis

“…Over the last decade, GWAS have identified only a few genetic loci associated with antipsychotic-induced weight gain [20][21][22][23][24]. These studies included a low number of participants and/or were restricted to patients taking one specific antipsychotic.…”