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. 2016 Dec;21(12):1717-1725.
doi: 10.1038/mp.2016.6. Epub 2016 Feb 23.

TSPAN5, ERICH3 and Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder: Pharmacometabolomics-Informed Pharmacogenomics

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Free PMC article

TSPAN5, ERICH3 and Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder: Pharmacometabolomics-Informed Pharmacogenomics

M Gupta et al. Mol Psychiatry. .
Free PMC article

Abstract

Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.

Figures

Figure 1
Figure 1
Patient plasma serotonin concentrations. Relative plasma serotonin concentrations (expressed as a ratio of the standard) in major depressive disorder patient samples were decreased significantly after 4 and 8 weeks of selective serotonin reuptake inhibitor treatment when compared with baseline. ***P<0.0001.
Figure 2
Figure 2
Baseline serotonin concentration GWAS. (a) GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant signal on chromosome 4 as well as a suggestive SNP cluster on chromosome 1. (b) The locus zoom shows that the SNPs on chromosome 1 are across ERICH3. The SNP most highly associated with baseline plasma serotonin concentration from this cluster was rs696692 (P=9.28E-08). (c) The locus zoom for the genome-wide significant SNP cluster on chromosome 4 shows that the SNPs are approximately 15–25 kb 5' of TSPAN5, with rs11947402 as the most highly associated with baseline plasma serotonin concentration (P=7.84E-09). GWAS, genome-wide association study; SNP, single nucleotide polymorphism.
Figure 3
Figure 3
TSPAN5 and ERICH3 SNP function. TSPAN5 expression is decreased for cells or tissues homozygous for variant (V/V) or with heterozygous (WT/V) SNP genotypes as compared with homozygous wild type (WT/WT) in (a) LCLs, (b) cerebral cortex and (c) frontal cortex. (d) Luciferase assay results comparing WT and variant SNP genotypes (rs1918743, rs59961429 and rs56095565) effects on transcriptional activities indicate decreased transcription for the variant TSPAN5 SNPs in SK-N-BE(2) neuroblastoma cells; (e) ERICH3 plasmids that were WT or contained one or both of the nonsynonymous SNPs (rs11580409 and rs11210490) were expressed in HEK-293T/17 cells. Both P264A (rs11210490) and L1056V (rs11580409) were associated with decreased protein levels as compared with WT, but L1056V was associated with a much greater decrease in protein level. (f) Quantification of ERICH3 protein relative to the GAPDH control for the ERICH3 western blots shown in (e). (g) Plasmids encoding ERICH3 allozymes that were WT or contained one or both of the amino acid substitutions (P264A and L1056V) were expressed in HEK-293T/17 cells with and without a protease inhibitor (MG132) or an autophagy inhibitor (3MA). MG132 prevented ERICH3 SNP-dependent protein degradation but 3MA did not. (h) Quantification of proteasome and autophagy inhibition of the ERICH3 allozyme degradation studies shown in (g). EV, empty vector; NS, non-significant; *P<0.05; **P<0.01; ***P<0.0001. LCL, lymphoblastoid cell lines; SNP, single nucleotide polymorphism.
Figure 4
Figure 4
TSPAN5 and ERICH3 association with serotonin biosynthesis and metabolism. (a) Serotonin biosynthesis and metabolism pathway. (b) mRNA expression of genes encoding serotonin pathway enzymes as measured by qRT-PCR were decreased after TSPAN5 KD (black) and increased after TSPAN5 OE (cross-hatched) in SK-N-BE(2) neuroblastoma cells. (c, d) Western blot analysis indicated decreased serotonin enzyme protein levels after TSPAN5 KD but no significant change after TSPAN5 OE, as quantified in (d). (e, f) Culture media serotonin concentrations after TSPAN5 (e) KD and (f) OE. (g, h) Cell culture media serotonin concentrations after ERICH3 (g) KD and (h) OE. *P<0.05; **P<0.01; TPH1/2, tryptophan hydroxylase 1/2; DDC, dopa decarboxylase; KD, knockdown; MAOA/B, monoamine oxidase A/B; OE, overexpression; SLC6A4, serotonin transporter; EV, empty vector.

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