Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder.
BACKGROUND
Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD).


METHODS
Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene-gene interactions.


RESULTS
Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value=0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene-gene interaction (P-value=0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value=0.015) among GNB3, HTR2A, and SLC6A4.


CONCLUSIONS
These results support the hypothesis that GNB3, HTR2A, and SLC6A4 may play a role in the outcome of short-term antidepressant treatment for MDD in an interactive manner. Future research with independent replication using large sample sizes is needed to confirm the functions of the candidate genes identified in this study as being involved in short-term antidepressant treatment response.
Lin
Eugene
E
Vita Genomics, Inc, Wugu Shiang, Taipei, Taiwan.
Chen
Po See
PS
Chang
Hui Hua
HH
Gean
Po-Wu
PW
Tsai
Hsin Chun
HC
Yang
Yen Kuang
YK
Lu
Ru-Band
RB
D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics; D012189:Retrospective Studies; D012701:Serotonin / Q000235:genetics* / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013624:Taiwan; D055815:Young Adult
D000928:Antidepressive Agents; C454420:G-protein beta3 subunit; D044302:Receptor, Serotonin, 5-HT1B; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D020962:Heterotrimeric GTP-Binding Proteins