Investigation of serotonin-related genes in antidepressant response

E. J. Peters, Susan L Slager, P. J. McGrath, J. A. Knowles, Steven P. Hamilton

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P = 0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P = 0.02-0.04) were positively associated and one SNP in the HTR2A gene (P = 0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P = 0.001-0.03) and two SNPs in the MAOA gene (P = 0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.

Original languageEnglish (US)
Pages (from-to)879-889
Number of pages11
JournalMolecular Psychiatry
Volume9
Issue number9
DOIs
StatePublished - Sep 2004

Fingerprint

Antidepressive Agents
Single Nucleotide Polymorphism
Serotonin
Fluoxetine
Genes
Haplotypes
Linkage Disequilibrium
Capillary Electrophoresis
Depressive Disorder
Sample Size
Alleles
Odds Ratio
Phenotype

Keywords

  • Antidepressant
  • Association
  • Linkage disequilibrium
  • Pharmacogenetic
  • SNP, haplotype

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health

Cite this

Investigation of serotonin-related genes in antidepressant response. / Peters, E. J.; Slager, Susan L; McGrath, P. J.; Knowles, J. A.; Hamilton, Steven P.

In: Molecular Psychiatry, Vol. 9, No. 9, 09.2004, p. 879-889.

Research output: Contribution to journalArticle

Peters, EJ, Slager, SL, McGrath, PJ, Knowles, JA & Hamilton, SP 2004, 'Investigation of serotonin-related genes in antidepressant response', Molecular Psychiatry, vol. 9, no. 9, pp. 879-889. https://doi.org/10.1038/sj.mp.4001502
Peters, E. J. ; Slager, Susan L ; McGrath, P. J. ; Knowles, J. A. ; Hamilton, Steven P. / Investigation of serotonin-related genes in antidepressant response. In: Molecular Psychiatry. 2004 ; Vol. 9, No. 9. pp. 879-889.
@article{bb3aa60952f14f029c890ec0780f53c6,
title = "Investigation of serotonin-related genes in antidepressant response",
abstract = "In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P = 0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P = 0.02-0.04) were positively associated and one SNP in the HTR2A gene (P = 0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P = 0.001-0.03) and two SNPs in the MAOA gene (P = 0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.",
keywords = "Antidepressant, Association, Linkage disequilibrium, Pharmacogenetic, SNP, haplotype",
author = "Peters, {E. J.} and Slager, {Susan L} and McGrath, {P. J.} and Knowles, {J. A.} and Hamilton, {Steven P.}",
year = "2004",
month = "9",
doi = "10.1038/sj.mp.4001502",
language = "English (US)",
volume = "9",
pages = "879--889",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Investigation of serotonin-related genes in antidepressant response

AU - Peters, E. J.

AU - Slager, Susan L

AU - McGrath, P. J.

AU - Knowles, J. A.

AU - Hamilton, Steven P.

PY - 2004/9

Y1 - 2004/9

N2 - In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P = 0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P = 0.02-0.04) were positively associated and one SNP in the HTR2A gene (P = 0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P = 0.001-0.03) and two SNPs in the MAOA gene (P = 0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.

AB - In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P = 0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P = 0.02-0.04) were positively associated and one SNP in the HTR2A gene (P = 0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P = 0.001-0.03) and two SNPs in the MAOA gene (P = 0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.

KW - Antidepressant

KW - Association

KW - Linkage disequilibrium

KW - Pharmacogenetic

KW - SNP, haplotype

UR - http://www.scopus.com/inward/record.url?scp=4644303054&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4644303054&partnerID=8YFLogxK

U2 - 10.1038/sj.mp.4001502

DO - 10.1038/sj.mp.4001502

M3 - Article

C2 - 15052272

AN - SCOPUS:4644303054

VL - 9

SP - 879

EP - 889

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 9

ER -