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.

Fig. 1

Effect of minor allele frequency on tagging single nucleotide polymorphism (SNP) selection. The above histogram displays the number of SNPs (N=145 total) at each minor allele frequency bin (solid black bars). The striped bars indicate the number of SNPs, in each minor allele frequency bin, which were selected as tagSNPs using the method of Carlson et al. [18].

Fig. 2

Accuracy of haplotype inference for three sets of tagging single nucleotide polymorphism (SNPs). Each of the eight haplotype blocks is shown on the x-axis. The minimum haplotype $R_h^2$ value for all common haplotypes within each block, inferred using the tagSNP set, is shown on the y-axis. Three different methods for selection of tagSNPs are shown (see Methods). Owing to the fact that methods of Carlson et al. [18] and Ke and Cardon [21] do not output a unique set of tagSNPs, average (±SD) minimum $R_h^2$ of all unique combinations of tagSNPs are shown.