Convergent Animal and Human Evidence Suggests a Role of PPM1A Gene in Response to Antidepressants

被引：29

作者：

Malki, Karim ^{[1
]}

Uher, Rudolf ^{[1
]}

Paya-Cano, Jose ^{[1
]}

Binder, Elke ^{[2
]}

Rietschel, Marcella ^{[3
]}

Zobel, Astrid ^{[4
]}

Mors, Ole ^{[5
]}

Hauser, Joanna ^{[6
]}

Henigsberg, Neven ^{[7
]}

Jerman, Borut ^{[8
]}

Souery, Daniel ^{[9
]}

Placentino, Anna ^{[10
,11
]}

Ng, Mandy Y. ^{[1
]}

Cohen-Woods, Sarah ^{[1
]}

Sluyter, Frans ^{[1
]}

Farmer, Anne ^{[1
]}

Aitchison, Katherine J. ^{[1
]}

Craig, Ian W. ^{[1
]}

Lewis, Cathryn M. ^{[1
]}

McGuffin, Peter ^{[1
]}

Schalkwyk, Leonard C. ^{[1
]}

机构：

[1] Kings Coll London, Inst Psychiat, London, England

[2] Univ Bordeaux, INSERM, Bordeaux, France

[3] Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, Mannheim, Germany

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

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

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

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

[8] Jozef Stefan Inst, Ljubljana, Slovenia

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

[10] Spedali Civili Hosp, Dept Mental Hlth, Psychiat Unit 23, Brescia, Italy

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

来源：

BIOLOGICAL PSYCHIATRY | 2011年 / 69卷 / 04期

关键词：

Antidepressants; escitalopram; GENDEP; nortriptyline; pharmacogenetic; PPM1A; STAR-ASTERISK-D; SEROTONIN REUPTAKE INHIBITOR; WHOLE-GENOME ASSOCIATION; DRUG RESPONSE; DEPRESSION; PHARMACOGENETICS; ESCITALOPRAM; PREDICTORS; CITALOPRAM; RECEPTOR;

D O I：

10.1016/j.biopsych.2010.08.011

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Background: Antidepressant drugs are used as first-line treatment in depression, but response has been shown to be highly heterogeneous, with drugs often failing to have the desired therapeutic effect. We report on an integrative analysis from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study using gene expression from mice to inform prioritization in a human pharmacogenetic study. Methods: The same two antidepressants were used in mice and humans: escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). The animal study used four inbred strains of mice (129S1/SvImJ, C57LB/6J, DBA/2J, and FVB/NJ). Hippocampus mRNA levels were measured in 144 animals using the Affymetrix MOE 430 v2 chip. Results: Based on gene-expression analysis of strain-by-drug interactions, 17 genes differentially expressed with nortriptyline or escitalopram versus saline were prioritized in the human pharmacogenetic analysis. Single nucleotide polymorphisms tagging common sequence variation in human orthologs of these genes were tested for association with response to antidepressants in 706 participants of the GENDEP human pharmacogenetic study, treated with escitalopram or nortriptyline for 12 weeks, with available high-quality Illumina 610 quad array genotyping. Several polymorphisms in the protein phosphatase 1A gene (PPM1A) remained significantly associated with response to nortriptyline in humans after correction for multiple comparisons within the gene. PPM1A encodes a phosphatase involved in mitogen-activated protein kinase signaling and cell stress response. C onclusions: Convergent evidence from mice and humans suggests a role of the PPM1A in response to noradrenergic but not serotonergic antidepressants.

引用

页码：360 / 365

页数：6

共 34 条

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