Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D

Affecting about 1 in 12 Americans annually, depression is a leading cause of the global disease burden. While a range of effective antidepressants are now available, failure and relapse rates remain substantial, with intolerable side effect burden the most commonly cited reason for discontinuation....

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Main Authors:	Adkins, D E, Clark, S L, Åberg, K, Hettema, J M, Bukszár, J, McClay, J L, Souza, R P, van den Oord, E J C G
Format:	Online
Language:	English
Published:	Nature Publishing Group 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410623/

id	pubmed-3410623
recordtype	oai_dc
spelling	pubmed-34106232012-08-02 Genome-wide pharmacogenomic study of citalopram-induced side effects in STARD Adkins, D E Clark, S L Åberg, K Hettema, J M Bukszár, J McClay, J L Souza, R P van den Oord, E J C G Original Article Affecting about 1 in 12 Americans annually, depression is a leading cause of the global disease burden. While a range of effective antidepressants are now available, failure and relapse rates remain substantial, with intolerable side effect burden the most commonly cited reason for discontinuation. Thus, understanding individual differences in susceptibility to antidepressant therapy side effects will be essential to optimize depression treatment. Here we perform genome-wide association studies (GWAS) to identify genetic variation influencing susceptibility to citalopram-induced side effects. The analysis sample consisted of 1762 depression patients, successfully genotyped for 421K single-nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study. Outcomes included five indicators of citalopram side effects: general side effect burden, overall tolerability, sexual side effects, dizziness and vision/hearing side effects. Two SNPs met our genome-wide significance criterion (q<0.1), ensuring that, on average, only 10% of significant findings are false discoveries. In total, 12 additional SNPs demonstrated suggestive associations (q<0.5). The top finding was rs17135437, an intronic SNP within EMID2, mediating the effects of citalopram on vision/hearing side effects (P=3.27 × 10−8, q=0.026). The second genome-wide significant finding, representing a haplotype spanning ∼30 kb and eight genotyped SNPs in a gene desert on chromosome 13, was associated with general side effect burden (P=3.22 × 10−7, q=0.096). Suggestive findings were also found for SNPs at LAMA1, AOX2P, EGFLAM, FHIT and RTP2. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antidepressant medications. Nature Publishing Group 2012-07 2012-07-03 /pmc/articles/PMC3410623/ /pubmed/22760553 http://dx.doi.org/10.1038/tp.2012.57 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Adkins, D E Clark, S L Åberg, K Hettema, J M Bukszár, J McClay, J L Souza, R P van den Oord, E J C G
spellingShingle	Adkins, D E Clark, S L Åberg, K Hettema, J M Bukszár, J McClay, J L Souza, R P van den Oord, E J C G Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D
author_facet	Adkins, D E Clark, S L Åberg, K Hettema, J M Bukszár, J McClay, J L Souza, R P van den Oord, E J C G
author_sort	Adkins, D E
title	Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D
title_short	Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D
title_full	Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D
title_fullStr	Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D
title_full_unstemmed	Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D
title_sort	genome-wide pharmacogenomic study of citalopram-induced side effects in star*d
description	Affecting about 1 in 12 Americans annually, depression is a leading cause of the global disease burden. While a range of effective antidepressants are now available, failure and relapse rates remain substantial, with intolerable side effect burden the most commonly cited reason for discontinuation. Thus, understanding individual differences in susceptibility to antidepressant therapy side effects will be essential to optimize depression treatment. Here we perform genome-wide association studies (GWAS) to identify genetic variation influencing susceptibility to citalopram-induced side effects. The analysis sample consisted of 1762 depression patients, successfully genotyped for 421K single-nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Outcomes included five indicators of citalopram side effects: general side effect burden, overall tolerability, sexual side effects, dizziness and vision/hearing side effects. Two SNPs met our genome-wide significance criterion (q<0.1), ensuring that, on average, only 10% of significant findings are false discoveries. In total, 12 additional SNPs demonstrated suggestive associations (q<0.5). The top finding was rs17135437, an intronic SNP within EMID2, mediating the effects of citalopram on vision/hearing side effects (P=3.27 × 10−8, q=0.026). The second genome-wide significant finding, representing a haplotype spanning ∼30 kb and eight genotyped SNPs in a gene desert on chromosome 13, was associated with general side effect burden (P=3.22 × 10−7, q=0.096). Suggestive findings were also found for SNPs at LAMA1, AOX2P, EGFLAM, FHIT and RTP2. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antidepressant medications.
publisher	Nature Publishing Group
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410623/
_version_	1611547252201881600

Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D

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