Abstract
Achieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.
Highlights
Achieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result
We identified a novel loss of function (LOF) variant in KRTAP1-1, keratin-associated protein 1–1, that is associated with outcome of selective serotonin reuptake inhibitors (SSRIs) antidepressant therapy in patients with MDD
Its association with the treatment outcome of SSRI antidepressant therapy was validated in an independent set of patients with MDD (Table 1, Supplementary Table S8)
Summary
Achieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Genetic variants found in previous genome-wide association studies (GWASs) on the antidepressant response do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings[10,11,12,13,14,15,16]. Here, we conducted a preliminary WGS study to identify genetic variants associated with remission following antidepressant treatment in a discovery set with a small sample size (n = 100) along with a replication set (n = 553). Our hypothesis was that genetic germline variants found using WGS might be associated with remission following antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs)
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