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Genome-wide pharmacogenetics of antidepressant response in the GENDEP project

Uher, Rudolf
Ng, Mandy Y. M.
Hauser, Joanna
Henigsberg, Neven
Maier, Wolfgang
Mors, Ole
Placentino, Anna
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Published in American Journal of Psychiatry. 2010, vol. 167, no. 5, p. 555-564
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. 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.
Keywords Antidepressive Agents/*therapeutic useAntidepressive Agents, Second-Generation/therapeutic useCitalopram/therapeutic useDepressive Disorder/*drug therapy/geneticsDepressive Disorder, Major/drug therapy/genetics*Genome-Wide Association StudyGenotypeHumansInterleukin-11/geneticsInterleukin-6/geneticsNortriptyline/therapeutic useOligonucleotide Array Sequence AnalysisPharmacogenetics/methodsPhenotypePolymorphism, Single Nucleotide/geneticsPsychiatric Status Rating ScalesSulfotransferases/geneticsTreatment Outcome
PMID: 20360315
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UHER, Rudolf et al. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. In: American Journal of Psychiatry, 2010, vol. 167, n° 5, p. 555-564. doi: 10.1176/appi.ajp.2009.09070932 https://archive-ouverte.unige.ch/unige:20578

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Deposited on : 2012-05-22

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