Abstract
We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n=711) revealed GWAS significance (P=1.60 × 10-8) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n=870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P=3.57 × 10-8). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20–0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.
Highlights
Response rates in drug treatment of major depression are unsatisfactory.[1]
The remission rate as a proportion of the response rate was 0.63 in the discovery set, 0.67 in the replication set and 0.59 in the cross-replication set. These proportions are typical of antidepressant trials[29] and they suggest that rating bias was not present
In this study we investigated the whole genomic associations of antidepressant response to selective serotonin reuptake inhibitor (SSRI)
Summary
Response rates in drug treatment of major depression are unsatisfactory.[1]. Initial antidepressant treatments fail in at least one-third of patients.[2]. Most pharmacogenetic studies that have focused on a few candidate genes (for example, serotonin transporter gene, SLC6A4) have shown results that lack sufficient predictive power to be useful in clinical practice.[6] Recently, several genome-wide pharmacogenetic studies of antidepressant treatment in major depressive disorder (MDD) were conducted to overcome these limitations.[7,8,9,10,11] none of their full-sample results reached genome-wide levels of statistical significance, and the top results were inconsistent.[6] These failures underscore the heterogeneous phenotype and the complex nature of clinical depression. These large, multisite studies risk being confounded by heterogeneity of case material, ethnicity and recruitment practices.[12,13]
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