A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.
Adult
Aged
Aged, 80 and over
Animals
Citalopram
/ therapeutic use
Depressive Disorder, Major
/ drug therapy
Female
Fluoxetine
/ therapeutic use
Humans
Male
Middle Aged
Paroxetine
/ therapeutic use
Receptors, Serotonin
/ genetics
Retrospective Studies
Selective Serotonin Reuptake Inhibitors
/ pharmacology
Sertraline
/ therapeutic use
Young Adult
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
24
11
2018
accepted:
21
02
2019
revised:
18
02
2019
pubmed:
16
3
2019
medline:
10
3
2021
entrez:
16
3
2019
Statut:
ppublish
Résumé
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 the 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 TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.
Identifiants
pubmed: 30874608
doi: 10.1038/s41380-019-0397-1
pii: 10.1038/s41380-019-0397-1
pmc: PMC6745302
mid: NIHMS1522410
doi:
Substances chimiques
Receptors, Serotonin
0
Serotonin Uptake Inhibitors
0
serotonin 7 receptor
0
Fluoxetine
01K63SUP8D
Citalopram
0DHU5B8D6V
Paroxetine
41VRH5220H
Sertraline
QUC7NX6WMB
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1312-1322Subventions
Organisme : NIMH NIH HHS
ID : U01 MH092758
Pays : United States
Organisme : Medical Research Council
ID : G0701420
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
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