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

• Published in: Molecular psychiatry Vol. 25; no. 6; pp. 1312 - 1322
• Main Authors: Wei, Ya Bin, McCarthy, Michael, Ren, Hongyan, Carrillo-Roa, Tania, Shekhtman, Tatyana, DeModena, Anna, Liu, Jia Jia, Leckband, Susan G., Mors, Ole, Rietschel, Marcella, Henigsberg, Neven, Cattaneo, Annamaria, Binder, Elisabeth B., Aitchison, Katherine J., Kelsoe, John R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 38/43; 45/29; 45/44; 45/77; 631/208; 631/337; 692/53/2423; 692/699/476/1333; 692/699/476/1414; 96/109; Adult; Aged; Aged, 80 and over; Alleles; Amoxapine; Animals; Antidepressants; Aripiprazole; Behavioral Sciences; Biological Psychology; Bipolar disorder; CCAAT/enhancer-binding protein; Cell lines; Citalopram; Citalopram - therapeutic use; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Electrophoretic mobility; Female; Fluoxetine; Fluoxetine - therapeutic use; Gender; Genes; Genetic aspects; Genetic diversity; Genetic research; Genomes; Genomics; Humans; Male; Medical colleges; Medicine; Medicine & Public Health; Mental depression; Middle Aged; Mood; Neurosciences; Paroxetine; Paroxetine - therapeutic use; Pharmacogenomics; Pharmacotherapy; Phenols; Phenotypes; Protein binding; Psychiatry; Receptors, Serotonin - genetics; Regulatory sequences; Retrospective Studies; Scientific equipment and supplies industry; Serotonin; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; Sertraline; Sertraline - therapeutic use; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Young Adult; United States; Germany; California
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-019-0397-1

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.