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Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

ABSTRACT: Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

SUBMITTER: Adkins DE

PROVIDER: S-EPMC2891163 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

Adkins D E DE Aberg K K McClay J L JL Bukszár J J Zhao Z Z Jia P P Stroup T S TS Perkins D D McEvoy J P JP Lieberman J A JA Sullivan P F PF van den Oord E J C G EJ

Molecular psychiatry 20100302 3

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical ...[more]

PMID: 20195266

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Project description:ObjectivesTo measure the incidence of movement side effects of antipsychotic drugs in adults with intellectual disability and compare rates with adults without intellectual disability.DesignCohort study using data from The Health Improvement Network.SettingUK primary care.ParticipantsAdults with intellectual disability prescribed antipsychotic drugs matched to a control group of adults without intellectual disability prescribed antipsychotic drugs.Outcome measuresNew records of movement side effect including acute dystonias, akathisia, parkinsonism, tardive dyskinaesia and neuroleptic malignant syndrome.Results9013 adults with intellectual disability and a control cohort of 34 242 adults without intellectual disability together contributed 148 709 person-years data. The overall incidence of recorded movement side effects was 275 per 10 000 person-years (95% CI 256 to 296) in the intellectual disability group and 248 per 10 000 person-years (95% CI 237 to 260) in the control group. The incidence of any recorded movement side effect was significantly greater in people with intellectual disability compared with those without (incidence rate ratio 1.30, 95% CI 1.18 to 1.42, p<0.001, after adjustment for potential confounders), with parkinsonism and akathisia showing the greatest difference between the groups. Neuroleptic malignant syndrome, although occurring infrequently, was three times more common in people with intellectual disability-prescribed antipsychotic drugs (incidence rate ratio 3.03, 95% CI 1.26 to 7.30, p=0.013). Differences in rates of movement side effects between the groups were not due to differences in the proportions prescribed first and second-generation antipsychotic drugs.ConclusionsThis study provides evidence to substantiate the long-held assumption that people with intellectual disability are more susceptible to movement side effects of antipsychotic drugs. Assessment for movement side effects should be integral to antipsychotic drug monitoring in people with intellectual disability. Regular medication review is essential to ensure optimal prescribing in this group.

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Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

Publications

Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.

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