title: Genome-wide pharmacogenetics of antidepressant response in the GENDEP project.
abstract: 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.
authors.affiliation: 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
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Nader
authors.initials: N
authors.lastname: Perroud
authors.forename: Mandy Y M
authors.initials: MY
authors.lastname: Ng
authors.forename: Joanna
authors.initials: J
authors.lastname: Hauser
authors.forename: Neven
authors.initials: N
authors.lastname: Henigsberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.forename: Anna
authors.initials: A
authors.lastname: Placentino
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Daniel
authors.initials: D
authors.lastname: Souery
authors.forename: Tina
authors.initials: T
authors.lastname: Zagar
authors.forename: Piotr M
authors.initials: PM
authors.lastname: Czerski
authors.forename: Borut
authors.initials: B
authors.lastname: Jerman
authors.forename: Erik Roj
authors.initials: ER
authors.lastname: Larsen
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.forename: Astrid
authors.initials: A
authors.lastname: Zobel
authors.forename: Sarah
authors.initials: S
authors.lastname: Cohen-Woods
authors.forename: Katrina
authors.initials: K
authors.lastname: Pirlo
authors.forename: Amy W
authors.initials: AW
authors.lastname: Butler
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Muglia
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barnes
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Anne
authors.initials: A
authors.lastname: Farmer
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
authors.forename: Ian
authors.initials: I
authors.lastname: Craig
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
mesh_terms: 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
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D017370:Interleukin-11; D015850:Interleukin-6; D015283:Citalopram; D009661:Nortriptyline; D015238:Sulfotransferases; C118596:UST protein, human