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 singlenucleotide 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 ¼ 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 ¼ 0.02-0.04) were positively associated and one SNP in the HTR2A gene (P ¼ 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 ¼ 0.001-0.03) and two SNPs in the MAOA gene (P ¼ 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.

Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR

“…39,41,42,58 Clinical association studies have further examined the relationship between SERTLPR alleles and psychiatric disorders and anxiety-related personality traits, [59][60][61][62][63][64][65][66] suicide, 67,68 alcoholism, 69,70 response to antidepressants [71][72][73] and brain function as revealed by MRI scans. [74][75][76][77] Although many studies have reported correlations between SERTLPR alleles and SERT expression levels or clinical phenotype, almost an equal number of studies have not.…”

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

“…Although not covering the locus systematically, several previous studies have provided suggestive evidence for an involvement of other HTR2A variants in antidepressant outcome (Minov et al, 2001;Cusin et al, 2002;Peters et al, 2004;Choi et al, 2005;Hong et al, 2006;Kato et al, 2006;McMahon et al, 2006;Paddock et al, 2007;Perlis et al, 2009). Post-mortem (McKeith et al, 1987Lopez-Figueroa et al, 2004) and positron emission tomography (PET) (Yates et al, 1990;Yatham et al, 2000;Mintun et al, 2004) studies have reported both increased and decreased HTR2A receptor number and binding in different brain regions of depressed individuals.…”

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…39,40 A wider list of polymorphism should be investigated to achieve a better resolution given that other control regions may be present for the 5-HTT expression, not to mention possible enhancers or silencers located in other regions far from the gene locus. In fact, Hamilton et al 28,41 reported a significant association of a functional SNP (rs25531) 42,43 located just upstream of the 5-HTTLPR with antidepressant response to fluoxetine treatment and in linkage disequilibrium (LD) with 5-HTTLPR. In the presence of the g allele of this SNP, the l allele of 5-HTTLPR seems to be associated with nonresponse, while this is the case for the s allele in presence of the a allele of the SNP.…”