Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes

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.

Integration of Whole-Exome Sequencing and Structural Neuroimaging Analysis in Major Depressive Disorder: A Joint Study

“…Pro les of germline variants and MDD-related genes After the systematic literature review, a total of 44 MDD-related genes were identi ed, and 40 of the 44 genes were found in the current study in 367 patients with MDD (Supplementary Table S1) [4,5,13,[35][36][37][38][39][40][41][42][43]. Rare exonic missense variants (with MAF less than 1%) of these genes were selected using the 1000 Genomes Project data, the Korean Variant Archive [44], and the Genome Aggregation Database.…”

Exploring mood disorders and treatment options using human stem cells

“…The current consensus of how MDD develops in an individual and the causes of the disorder are a culmination of genetic, psychological, and environmental factors ( Bromet et al, 2011 ). MDD acts on the brain and most notably affects the process of neurotransmitters and synaptic activity in the forebrain region ( Park et al, 2021 ). Neurotransmitters, like serotonin, norepinephrine, and dopamine, are essential for regulating the central nervous system (CNS) ( Goldstein et al, 2015 ).…”

“…A significant portion of those diagnosed with MDD are thought to be genetically predisposed to the disorder, as MDD is known to affect entire families in some cases ( Klein et al, 2001 ). Genetic studies have shown that MDD has a significant overlap with genes associated with other psychiatric disorders ( Park et al, 2021 ). The genetics of major depressive disorder reveal polygenic risk scores on an individual basis, but there is no official manner of treatment or diagnosis provided through one’s genetics ( Fabbri et al, 2020 ).…”

Gender variation in whole genome sequencing of susceptibility genes in a rat model of depression

“…Whole genome sequencing (WGS) can provide information regarding all genetic variants-rare variants, loss of function (LOF), functional intronic variants, and structural variants. Significant outcomes from studies on these variants can provide useful information to pinpoint causal genes and their associated pathways (Park et al, 2021). Hence, this study aims to explore whole genome sequencing in male and female Wistar rats susceptible to depression.…”