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Targeted pharmacogenetic analysis of antipsychotic response in the CATIE study.

ABSTRACT: This study evaluated the impact of 6789 SNPs on treatment response to antipsychotics in Caucasian patients from the CATIE study.An Illumina (CA, USA) BeadChip was designed that targeted genes potentially impacting disease risk, disease presentation or antipsychotic response. SNPs tagged regions of linkage disequilibrium or functional variants not detectable using previous genotypes for CATIE. Change in Positive and Negative Syndrome scale total score was modeled using a mixed model repeated measures method that assumed a 30-day lag period. Genetic association analysis was performed using linear regression.Association analysis identified 20 SNPs with p-values of ?5 × 10(-4). Many of these are in genes previously implicated in schizophrenia and other neuropsychiatric diseases.The targeted approach identified SNPs possibly influencing response to antipsychotic drugs in Caucasian patients suffering from schizophrenia. The findings support a biological link between disease risk and presentation and antipsychotic response.

SUBMITTER: Liu Q

PROVIDER: S-EPMC3518380 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Targeted pharmacogenetic analysis of antipsychotic response in the CATIE study.

Liu Qian Q Jamba Maidar M Patrick Calvin C Padmanabhan Saranya S Brennan Mark D MD

Pharmacogenomics 20120801 11

<h4>Aim</h4>This study evaluated the impact of 6789 SNPs on treatment response to antipsychotics in Caucasian patients from the CATIE study.<h4>Materials & methods</h4>An Illumina (CA, USA) BeadChip was designed that targeted genes potentially impacting disease risk, disease presentation or antipsychotic response. SNPs tagged regions of linkage disequilibrium or functional variants not detectable using previous genotypes for CATIE. Change in Positive and Negative Syndrome scale total score was m ...[more]

PMID: 22920393

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Project description:Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

Dataset Information

Targeted pharmacogenetic analysis of antipsychotic response in the CATIE study.

Publications

Targeted pharmacogenetic analysis of antipsychotic response in the CATIE study.

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