Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D.
Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D.
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DOI：
10.1038/tp.2012.57
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发表时间：
2012-07-03
影响因子：
6.8
通讯作者：
van den Oord EJ
中科院分区：
文献类型：
--
作者：
Adkins DE;Clark SL;Åberg K;Hettema JM;Bukszár J;McClay JL;Souza RP;van den Oord EJ
抑郁症每年影响约1/12的美国人，是全球疾病负担的主要原因。虽然现在有一系列有效的抗抑郁药，但失败率和复发率仍然很高，无法忍受的副作用负担是最常见的停药原因。因此，了解抗抑郁药治疗副作用易感性的个体差异对于优化抑郁症治疗至关重要。在这里，我们进行全基因组关联研究（GWAS），以确定影响西酞普兰诱导的副作用的易感性的遗传变异。分析样本由1762名抑郁症患者组成，成功进行了421 K单核苷酸多态性（SNP）基因分型，来自缓解抑郁症的序贯治疗替代方案（星星 *D）研究。结果包括西酞普兰副作用的五个指标：一般副作用负担、总体耐受性、性副作用、头晕和视力/听力副作用。两个SNP符合我们的全基因组显著性标准（q<0.1），确保平均只有10%的重大发现是错误的发现。总共有12个额外的SNP表现出暗示性关联（q<0.5）。最重要的发现是rs 17135437，EMID 2内的内含子SNP，介导西酞普兰对视觉/听力副作用的影响（P=3.27 × 10−8，q=0.026）。第二个全基因组的显著发现，代表了13号染色体上基因沙漠中一个跨度为30 kb的单倍型和8个基因型SNP，与一般副作用负担相关（P=3.22 × 10−7，q=0.096）。在LAMA 1、AOX 2 P、EGFLAM、FHIT和RTP 2的SNP中也发现了提示性的发现。虽然我们的研究结果需要复制和功能验证，但这项研究证明了GWAS发现可能介导抗抑郁药物不良反应的基因和途径的潜力。
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.