Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis

被引：81

作者：

Tansey, Katherine E. ^{[1
]}

Guipponi, Michel ^{[2
]}

Perroud, Nader ^{[3
]}

Bondolfi, Guido ^{[3
]}

Domenici, Enrico ^{[4
,5
]}

Evans, David ^{[6
]}

Hall, Stephanie K. ^{[7
]}

Hauser, Joanna ^{[8
]}

Henigsberg, Neven ^{[9
]}

Hu, Xiaolan ^{[7
]}

Jerman, Borut ^{[10
,11
]}

Maier, Wolfgang ^{[12
]}

Mors, Ole ^{[13
]}

O'Donovan, Michael ^{[14
]}

Peters, Tim J. ^{[15
]}

Placentino, Anna ^{[16
,17
]}

Rietschel, Marcella ^{[18
]}

Souery, Daniel ^{[19
]}

Aitchison, Katherine J. ^{[1
,20
]}

Craig, Ian ^{[1
]}

Farmer, Anne ^{[1
]}

Wendland, Jens R. ^{[5
]}

Malafosse, Alain ^{[2
,3
]}

Holmans, Peter ^{[14
]}

Lewis, Glyn ^{[21
]}

Lewis, Cathryn M. ^{[1
]}

Stensbol, Tine Bryan ^{[22
]}

Kapur, Shitij ^{[1
]}

McGuffin, Peter ^{[1
]}

Uher, Rudolf ^{[1
,23
]}

机构：

[1] Kings Coll London, Inst Psychiat, London WC2R 2LS, England

[2] Univ Hosp Geneva, Dept Genet Med & Labs, Geneva, Switzerland

[3] Univ Geneva, Dept Psychiat, Geneva, Switzerland

[4] GlaxoSmithKline Med Res Ctr, Ctr Excellence Drug Discovery Psychiat, Verona, Italy

[5] F Hoffmann La Roche, Pharma Res & Early Dev, Basel, Switzerland

[6] Univ Bristol, Sch Social & Community Med, Med Res Council CAiTE Ctr, Bristol, Avon, England

[7] Pfizer Inc, Mol Med, Groton, CT 06340 USA

[8] Poznan Univ Med Sci, Lab Psychiat Genet, Poznan, Poland

[9] Univ Zagreb, Croatian Inst Brain Res, Sch Med, Zagreb 41000, Croatia

[10] Jozef Stefan Inst, Dept Mol & Biomed Sci, Ljubljana 61000, Slovenia

[11] Inst Publ Hlth Republ Slovenia, Ljubljana, Slovenia

[12] Univ Bonn, Dept Psychiat, Bonn, Germany

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

[14] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff, S Glam, Wales

[15] Univ Bristol, Sch Clin Sci, Bristol, Avon, England

[16] Ctr San Giovanni di Dio Fatebenefratelli, Psychiat Unit 23, Dept Mental Hlth, Spedali Civili Hosp, Brescia, Italy

[17] Ctr San Giovanni di Dio Fatebenefratelli, Biol Psychiat Unit, Brescia, Italy

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

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

[20] Univ Alberta, Dept Psychiat, Edmonton, AB, Canada

[21] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England

[22] H Lundbeck & Co AS, Discovery Pharmacol Res, Copenhagen, Denmark

[23] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada

来源：

PLOS MEDICINE | 2012年 / 9卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

STAR-ASTERISK-D; CLINICAL-PRACTICE; GENDEP PROJECT; ASSOCIATION; PHARMACOGENETICS; REPLICATION; SEVERITY; OUTCOMES; SCALE;

D O I：

10.1371/journal.pmed.1001326

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. Methods and Findings: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5x10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p, 5610 28) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR* D. Conclusions: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.

引用

页数：10

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