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Convergent animal and human evidence suggests a role of PPM1A gene in response to antidepressants

Malki, K and Uher, R and Paya-Cano, J and Binder, E and Rietschel, M and Zobel, A and Mors, O and Hauser, J and Henigsberg, N and Jerman, B and Souery, D and Placentino, A and Ng, MY and Cohen-Woods, S and Sluyter, F and Farmer, A and Aitchison, KJ and Craig, IW and Lewis, CM and McGuffin, P and Schalkwyk, LC (2011) 'Convergent animal and human evidence suggests a role of PPM1A gene in response to antidepressants.' Biological Psychiatry, 69 (4). 360 - 365. ISSN 0006-3223

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Abstract

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/SvlmJ, 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. Conclusions Convergent evidence from mice and humans suggests a role of the PPM1A in response to noradrenergic but not serotonergic antidepressants. © 2011 Society of Biological Psychiatry.

Item Type: Article
Subjects: Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 14 Nov 2014 16:46
Last Modified: 17 Aug 2017 17:46
URI: http://repository.essex.ac.uk/id/eprint/11063

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