Convergent animal and human evidence suggests a role of PPM1A gene in response to antidepressants.
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.
Institute of Psychiatry, King's College London, United Kingdom. karim.malki@iop.kcl.ac.uk
Karim
K
Malki
Rudolf
R
Uher
Jose
J
Paya-Cano
Elke
E
Binder
Marcella
M
Rietschel
Astrid
A
Zobel
Ole
O
Mors
Joanna
J
Hauser
Neven
N
Henigsberg
Borut
B
Jerman
Daniel
D
Souery
Anna
A
Placentino
Mandy Y
MY
Ng
Sarah
S
Cohen-Woods
Frans
F
Sluyter
Anne
A
Farmer
Katherine J
KJ
Aitchison
Ian W
IW
Craig
Cathryn M
CM
Lewis
Peter
P
McGuffin
Leonard C
LC
Schalkwyk
D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009661:Nortriptyline / Q000494:pharmacology / Q000627:therapeutic use*; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000928:Antidepressive Agents; D012333:RNA, Messenger; D015283:Citalopram; D009661:Nortriptyline; C000607456:PPM1A protein, human; D010749:Phosphoprotein Phosphatases; C000607466:Ppm1a protein, mouse; D000071636:Protein Phosphatase 2C