Genome-Wide Pharmacogenetics of Antidepressant Response in the GENDEP Project

• Published in: The American journal of psychiatry 2010-05, Vol.167 (5), p.555-564
• Main Authors: Uher, Rudolf, Perroud, Nader, Ng, Mandy Y.M., Hauser, Joanna, Henigsberg, Neven, Maier, Wolfgang, Mors, Ole, Placentino, Anna, Rietschel, Marcella, Souery, Daniel, Žagar, Tina, Czerski, Piotr M., Jerman, Borut, Larsen, Erik Roj, Schulze, Thomas G., Zobel, Astrid, Cohen-Woods, Sarah, Pirlo, Katrina, Butler, Amy W., Muglia, Pierandrea, Barnes, Michael R., Lathrop<, Mark, Farmer, Anne, Breen, Gerome, Aitchison, Katherine J., Craig, Ian, Lewis, Cathryn M., McGuffin, Peter
• Format: Article
• Language: English
• Subjects: Antidepressants; Antidepressive Agents - therapeutic use; Antidepressive Agents, Second-Generation - therapeutic use; Biological and medical sciences; Citalopram - therapeutic use; Depressive Disorder - drug therapy; Depressive Disorder - genetics; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Genes; Genetics; Genome-Wide Association Study; Genotype; Humans; Interleukin-11 - genetics; Interleukin-6 - genetics; Medical sciences; Neuropharmacology; Nortriptyline - therapeutic use; Oligonucleotide Array Sequence Analysis; Pharmacogenetics - methods; Pharmacology. Drug treatments; Phenotype; Polymorphism, Single Nucleotide - genetics; Psychiatric Status Rating Scales; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Quality control; Serotonin; Studies; Sulfotransferases - genetics; Treatment Outcome
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.2009.09070932

ObjectiveThe 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. MethodHigh-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. ResultsSingle 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. ConclusionsWhile 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.