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

被引：34

作者：

Adkins, D. E. ^{[1
]}

Clark, S. L. ^{[1
]}

Aberg, K. ^{[1
]}

Hettema, J. M. ^{[2
]}

Bukszar, J. ^{[1
]}

McClay, J. L. ^{[1
]}

Souza, R. P. ^{[3
]}

van den Oord, E. J. C. G. ^{[1
]}

机构：

[1] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Sch Pharm, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA

[3] Univ Extremo Sul Catarinense, Neurosci Lab, Criciuma, Brazil

来源：

TRANSLATIONAL PSYCHIATRY | 2012年 / 2卷

关键词：

citalopram; depression; genome-wide association study; pharmacogenomics; side effects; STAR* D; FALSE DISCOVERY RATE; ASSOCIATION SCAN; GENE-EXPRESSION; DISORDERS; DEPRESSION; SEROTONIN; ANTIDEPRESSANTS; RISK; DISCONTINUATION; COMORBIDITY;

D O I：

10.1038/tp.2012.57

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

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 x 10(-8), q - 0.026). The second genome-wide significant finding, representing a haplotype spanning similar to 30 kb and eight genotyped SNPs in a gene desert on chromosome 13, was associated with general side effect burden (P = 3.22 x 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. Translational Psychiatry (2012) 2, e129; doi:10.1038/tp.2012.57; published online 3 July 2012

引用

页码：e129 / e129

页数：9

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