Genome-wide pharmacogenetics of antidepressant response in the GENDEP project

Rudolf Uher, Nader Perroud, Mandy Ng, Marian Neuhouser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Tina Zagar, Piotr Czerski, Borut Jerman, Erik Larson, Thomas Schulze, Astrid Zobel, Sarah Cohen-Woods, Katrina Pirlo, Amy Butler, Pierandrea MugliaMichael Barnes, Mark Lathrop, Anne Farmer, Gerome Breen, Katherine Aitchison, Ian Craig, Cathryn Lewis, Peter McGuffin

    Research output: Contribution to journalArticlepeer-review

    267 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)555-564
    Number of pages10
    JournalAmerican Journal of Psychiatry
    Volume167
    Issue number5
    DOIs
    Publication statusPublished - May 2010

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