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

Karim Malki, Rudolf Uher, Jose Paya-Cano, Elke Binder, Marcella Rietschel, Astrid Zobel, Ole Mors, Joanna Hauser, Neven Henigsberg, Borut Jerman, Daniel Souery, Anna Placentino, Mandy Y. Ng, Sarah Cohen-Woods, Frans Sluyter, Anne Farmer, Katherine J. Aitchison, Ian W. Craig, Cathryn M. Lewis, Peter McGuffinLeonard C. Schalkwyk

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageEnglish
Pages (from-to)360-365
Number of pages6
JournalBiological Psychiatry
Issue number4
StatePublished - 15 Feb 2011
Externally publishedYes


  • Antidepressants
  • PPM1A
  • escitalopram
  • nortriptyline
  • pharmacogenetic


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