A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression

Abstract

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n=359). We found 80 single nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI treated patients with major depressive disorder: the MARS (n=253, P=0.0169) and GENDEP studies (n=432, P=0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TF. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

“…Likewise, a very recent work showed that one single nucleotide polymorphism located in the promoter region of the 5-HT7R gene is associated with a better response to two antidepressants, paroxetine and fluoxetine, that are selective 5-HT reuptake inhibitors. These data provide novel pharmacogenomic evidence to support the role of 5-HT7R in antidepressant response [86].…”

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

“…Likewise, a very recent work showed that one single nucleotide polymorphisms located in the promoter region of the 5-HT7R gene is associated with better response to two antidepressants, paroxetine and fluoxetine, that are selective 5-HT reuptake inhibitors. These data provide novel pharmacogenomic evidence to support the role of 5-HT7R in antidepressant response [83]. However, pharmacological and genetic manipulation of 5-HT7R in animal models of depression, anxiety and schizophrenia has often given inconsistent or conflicting results.…”

Implication of 5-HT7 receptor in prefrontal circuit assembly and detrimental emotional effects of SSRIs during development

“…Furthermore, a variant of 5-HTR7 has been associated to a better response to SSRIs in bipolar patients [29].…”

“…Moreover, 5-HTR7 has been implicated in mood control, based on pharmacological studies showing that antagonizing 5-HTR7 attenuates anxiety and depression-like phenotypes [ 25 – 28 ]. Furthermore, a variant of 5-HTR7 has been associated to a better response to SSRIs in bipolar patients [ 29 ].…”