Genetic predictors of response to antidepressants in the GENDEP project

被引：161

作者：

Uher, Rudolf ^{[1
]}

Huezo-Diaz, Patricia

Perroud, Nader

Smith, Rebecca

Rietschel, Marcella ^{[2
]}

Mors, Ole ^{[3
]}

Hauser, Joanna ^{[4
]}

Maier, Wolfgang ^{[5
]}

Kozel, Dejan ^{[6
]}

Henigsberg, Neven ^{[7
]}

Barreto, Mara ^{[8
]}

Placentino, Anna ^{[9
]}

Dernovsek, Mojca Zvezdana ^{[10
]}

Schulze, Thomas G. ^{[2
]}

Kalember, Petra ^{[7
]}

Zobel, Astrid ^{[5
]}

Czerski, Piotr M. ^{[4
]}

Larsen, Erik Roj ^{[11
]}

Souery, Daniel ^{[12
]}

Giovannini, Caterina ^{[9
]}

Gray, Joanna M.

Lewis, Cathryn M.

Farmer, Anne

Aitchison, Katherine J.

McGuffin, Peter

Craig, Ian

机构：

[1] Kings Coll London, Dept Social Genet & Dev Psychiat, Inst Psychiat, MRC Social Genet & Dev Psychiat Ctr, London SE5 8AF, England

[2] Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, D-6800 Mannheim, Germany

[3] Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark

[4] Poznan Univ Med Sci, Lab Psychiat Genet, Dept Psychiat, Poznan, Poland

[5] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany

[6] Ctr Community Hlth, Prevent Unit CINDI, Ljubljana, Slovenia

[7] Univ Zagreb, Sch Med, Dept Neuropharmacol & Behav Pharmacol, Croatian Inst Brain Res, Zagreb 41001, Croatia

[8] Univ Libre Bruxelles, Erasme Acad Hosp, Dept Psychiat, Brussels, Belgium

[9] Ctr San Giovanni Dio Fatebenefratelli, Ist Ricovero & Cura Carattere Sci, Dept Psychiat, Biol Psychiat Unit & Dual Diag Ward, Brescia, Italy

[10] Educ & Res Inst Ozara, Ljubljana, Slovenia

[11] Aarhus Univ Hosp, Clin Chron Depress, Risskov, Denmark

[12] Univ Libre Bruxelles & Psy Pluriel, Ctr Europeen Psychol Med, Lab Psychol Med, Brussels, Belgium

来源：

PHARMACOGENOMICS JOURNAL | 2009年 / 9卷 / 04期

关键词：

depression; antidepressants; pharmacogenetics; serotonin; norepinephrine; glucocorticoid receptor; SEROTONIN REUPTAKE INHIBITOR; FALSE DISCOVERY RATE; MAJOR DEPRESSION; POLYMORPHISMS; ASSOCIATION; RECEPTOR; ESCITALOPRAM; EFFICACY; LINKAGE;

D O I：

10.1038/tpj.2009.12

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P = 0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction. The Pharmacogenomics Journal (2009) 9, 225-233; doi: 10.1038/tpj.2009.12; published online 14 April 2009

引用

页码：225 / 233

页数：9

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