Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics

Abstract

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻⁶). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻⁵). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

Figure 1

Manhattan plots of −log10(p-values) from logistic regression adjusted for eigenvectors versus chromosomal position of SNPs. (a) Manhattan plot of −log10(p-values) for GWA analysis of eight-week SSRI response outcome. (b) Manhattan plot of −log10(p-values) for GWA analysis of eight-week SSRI remission outcome. Red dots represent SNPs with p-values ≤ 10⁻⁵ and blue dots represent SNPs with p-values ≤ 10⁻⁴.

Figure 2

Functional genomics of candidate SNPs. (a) A table to summarize the 14 SNPs that were selected for functional genomic studies. (b) Results of dual-luciferase reporter gene assays for SNPs rs11144870, rs11144905, rs2248399, rs915120 and rs12254134, performed in the neuroblastoma SK-N-BE(2) cell line. Each bar represents the average of relative luciferase activity reported as a % of the pGL3-Promoter construct activity obtained during 6 independent transfections (mean ± S.E.M). ** represents p-values < 0.01 compared to values for pGL3-WT activity. (b) Electrophoretic mobility shift (EMS) assays for SNPs rs11144870, rs785916 (GCNT1), rs2248399 (DAOA), rs2248174 (DAOA), rs1998560 (DAOA), rs915120 (GRK5) and rs12254134 (GRK5) with nuclear extract prepared from SK-N-BE(2) cells.