Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response

Abstract

Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.

HTR2A is Associated with SSRI Response in Major Depressive Disorder in a Japanese Cohort

“…McMahon et al (2006) reported an association between rs7997012 and rs1928040 in HTR2A and the outcome of citalopram treatment in a very large sample of outpatients with MDD. Peters et al (2009) replicated those findings in a study showing that rs7997012 was associated with citalopram response in MDD. However, Perlis et al (2009) reported that rs7997012 and rs1928040 were not associated with duloxetine treatment outcome in MDD.…”

Tryptophan Hydroxylase as Novel Target for the Treatment of Depressive Disorders

“…However, whereas some studies show a significant link between a TPH2 SNP haplotype and specific responses to 5-HT reuptake inhibitors (SSRIs) [49,94,95], others, here again, do not confirm any association between this trait and TPH2 SNPs in various ethnic groups [60,62,72] .…”

“…The fact that the mutation is located within the part of the oligomerization domain that has previously been shown to be pivotal for TPH 2 activity [63] together with the description of a corresponding severe pathogenic mutation in PAH (R408W) led to the expectation that the first lossof-function mutation in human TPH2 had been identified [64] . However, this functional polymorphism could not be confirmed in any other study [62,[65][66][67][68][69][70][71][72] . Thus it is either a rare mutation within a very unique cohort with unipolar depression or the result of a genotyping error.…”

Pharmacogenetics of antidepressant response

“…259 Several other variants have been reported to predict antidepressant response. 85,117,134,179,229,260,261 Table 8 lists relevant genetic association studies that investigated the impact of these variations on the antidepressant response.…”