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Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.

ABSTRACT: Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain.Pharmacogenetic association study.The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial.The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects.Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.We conducted a genomewide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug-induced weight gain.Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P<10(-5). This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P=5.59 X 10 (-12). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels.These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.

SUBMITTER: Malhotra AK

PROVIDER: S-EPMC4166499 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.

Malhotra Anil K AK Correll Christoph U CU Chowdhury Nabilah I NI Müller Daniel J DJ Gregersen Peter K PK Lee Annette T AT Tiwari Arun K AK Kane John M JM Fleischhacker W Wolfgang WW Kahn Rene S RS Ophoff Roel A RA Meltzer Herbert Y HY Lencz Todd T Kennedy James L JL

Archives of general psychiatry 20120901 9

<h4>Context</h4>Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.<h4>Objective</h4>To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain.<h4>Design</h4>Pharmacogenetic association study.<h4>Setting</h4>The discovery cohort was from a US general ps ...[more]

PMID: 22566560

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Project description:RationaleWeight gain is a frequent side effect of treatment with SGAs (second-generation antipsychotics) and a leading cause for nonadherence. Several candidate genes have been identified that could influence the amount of AIWG (antipsychotic-induced weight gain). The polymorphism rs17782313 near the MC4R (human melanocortin 4 receptor gene) was strongly associated with obesity in a large scale GWAS (genome wide association study), yet previous studies investigating its impact on AIWG did not lead to a definite conclusion regarding its effect. In particular, they were all relatively short and had a naturalistic design.ObjectiveWe therefore examined the influence of the rs17782313 polymorphism on SGA-related weight gain.MethodsParticipants of a multicenter randomized, controlled, double-blind study comparing two treatment strategies in individuals with schizophrenia or schizoaffective disorder were genotyped using a rapid-cycle polymerase chain reaction. Up to 252 individuals completed the first 2 weeks (phase I), 212 the entire 8 weeks (hence 'completers'). Patients received either amisulpride or olanzapine or both consecutively. Thirty-seven had their first episode. Weight gain occurring in different genotypes was statistically compared and confounding factors were adjusted by stepwise multiple linear regression. A correction for multiple testing was included.ResultsWithin 212 'completers', carriers of the C allele had a higher absolute weight gain than those homozygous for the T allele (2.6 kg vs. 1.2 kg), though this observation was not significant (P = 0.063). In the amisulpride subpopulation, this association appeared stronger and reached significance (2.5 kg vs. 0.7 kg, P = 0.043), though failed to remain significant after correction for multiple testing. A stepwise multiple linear regression showed a significant association in both the whole study population (P < 0.001) and the amisulpride subpopulation (P < 0.001).ConclusionOur results indicate that the rs17782313 polymorphism might influence antipsychotic-induced weight gain and therefore confirm some of the earlier conclusions.

Dataset Information

Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.

Publications

Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.

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