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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.

SUBMITTER: Peters EJ

PROVIDER: S-EPMC2896826 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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

Peters Eric J EJ Slager Susan L SL Jenkins Greg D GD Reinalda Megan S MS Garriock Holly A HA Shyn Stanley I SI Kraft Jeffrey B JB McGrath Patrick J PJ Hamilton Steven P SP

Pharmacogenetics and genomics 20090101 1

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 s ...[more]

PMID: 19077664

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Project description:Boar taint is an unpleasant odour and flavour of the meat from some uncastrated male pigs primarily caused by elevated levels of androstenone and skatole in adipose tissue. Androstenone is produced in the same biochemical pathway as testosterone and estrogens, which represents a particular challenge when selecting against high levels of androstenone in the breeding programme, without simultaneously decreasing levels of other steroids. Detection of single nucleotide polymorphisms (SNPs) associated with compounds affecting boar taint is important both for gaining a better understanding of the complex regulation of the trait and for the purpose of identifying markers that can be used to improve the gain of breeding. The beneficial SNPs to be used in breeding would have the combinational effects of reducing levels of boar taint without affecting fertility of the animals. The aim of this study was to detect SNPs in boar taint candidate genes and to perform association studies for both single SNPs and haplotypes with levels of boar taint compounds and phenotypes related to reproduction.An association study involving 275 SNPs in 121 genes and compounds related to boar taint and reproduction were carried out in Duroc and Norwegian Landrace boars. Phenotypes investigated were levels of androstenone, skatole and indole in adipose tissue, levels of androstenone, testosterone, estrone sulphate and 17beta-estradiol in plasma, and length of bulbo urethralis gland. The SNPs were genotyped in more than 2800 individuals and several SNPs were found to be significantly (LRT > 5.4) associated with the different phenotypes. Genes with significant SNPs in either of the traits investigated include cytochrome P450 members CYP2E1, CYP21, CYP2D6 and CYP2C49, steroid 5alpha-reductase SRD5A2, nuclear receptor NGFIB, catenin CTNND1, BRCA1 associated protein BAP1 and hyaluronoglucosaminidase HYAL2. Haplotype analysis provided additional evidence for an effect of CYP2E1 on levels of skatole and indole, and for BAP1, HYAL2 and SRD5A2 on levels of androstenone.The findings in this study indicate that polymorphisms in CYP2E1, CYP21, CYP2D6, CYP2C49, NGFIB and CTNND1 might be used to reduce levels of boar taint without affecting levels of testosterone, estrone sulphate, 17beta-estradiol or length of bulbo urethralis gland.

Dataset Information

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

Publications

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

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