Genome-wide pharmacogenetics of antidepressant response in the GENDEP project.
OBJECTIVE
The purpose of this study was to identify genetic variants underlying the considerable individual differences in response to antidepressant treatment. The authors performed a genome-wide association analysis of improvement of depression severity with two antidepressant drugs.


METHODS
High-quality Illumina Human610-quad chip genotyping data were available for 706 unrelated participants of European ancestry treated for major depression with escitalopram (N=394) or nortriptyline (N=312) over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a partially randomized open-label pharmacogenetic trial.


RESULTS
Single nucleotide polymorphisms in two intergenic regions containing copy number variants on chromosomes 1 and 10 were associated with the outcome of treatment with escitalopram or nortriptyline at suggestive levels of significance and with a high posterior likelihood of true association. Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene. A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11.


CONCLUSIONS
While limited statistical power means that a number of true associations may have been missed, these results suggest that efficacy of antidepressants may be predicted by genetic markers other than traditional candidates. Genome-wide studies, if properly replicated, may thus be important steps in the elucidation of the genetic basis of pharmacological response.
Uher
Rudolf
R
Medical Research Council Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, SE5 8AF, London, United Kingdom. rudolf.uher@iop.kcl.ac.uk
Perroud
Nader
N
Ng
Mandy Y M
MY
Hauser
Joanna
J
Henigsberg
Neven
N
Maier
Wolfgang
W
Mors
Ole
O
Placentino
Anna
A
Rietschel
Marcella
M
Souery
Daniel
D
Zagar
Tina
T
Czerski
Piotr M
PM
Jerman
Borut
B
Larsen
Erik Roj
ER
Schulze
Thomas G
TG
Zobel
Astrid
A
Cohen-Woods
Sarah
S
Pirlo
Katrina
K
Butler
Amy W
AW
Muglia
Pierandrea
P
Barnes
Michael R
MR
Lathrop
Mark
M
Farmer
Anne
A
Breen
Gerome
G
Aitchison
Katherine J
KJ
Craig
Ian
I
Lewis
Cathryn M
CM
McGuffin
Peter
P
D000928:Antidepressive Agents / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D015283:Citalopram / Q000627:therapeutic use; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D009661:Nortriptyline / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D015238:Sulfotransferases / Q000235:genetics; D016896:Treatment Outcome
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D017370:Interleukin-11; D015850:Interleukin-6; D015283:Citalopram; D009661:Nortriptyline; D015238:Sulfotransferases; C118596:UST protein, human