Scientific article

Genome-wide pharmacogenetics of antidepressant response in the GENDEP project

Published inThe American journal of psychiatry, vol. 167, no. 5, p. 555-564
Publication date2010

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. METHOD: 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.

  • Antidepressive Agents/*therapeutic use
  • Antidepressive Agents, Second-Generation/therapeutic use
  • Citalopram/therapeutic use
  • Depressive Disorder/*drug therapy/genetics
  • Depressive Disorder, Major/drug therapy/genetics
  • *Genome-Wide Association Study
  • Genotype
  • Humans
  • Interleukin-11/genetics
  • Interleukin-6/genetics
  • Nortriptyline/therapeutic use
  • Oligonucleotide Array Sequence Analysis
  • Pharmacogenetics/methods
  • Phenotype
  • Polymorphism, Single Nucleotide/genetics
  • Psychiatric Status Rating Scales
  • Sulfotransferases/genetics
  • Treatment Outcome
Citation (ISO format)
UHER, Rudolf et al. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. In: The American journal of psychiatry, 2010, vol. 167, n° 5, p. 555–564. doi: 10.1176/appi.ajp.2009.09070932
ISSN of the journal0002-953X

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