1. Genome-Wide Pharmacogenetics of Antidepressant Response in the GENDEP Project
- Author
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Neven Henigsberg, Cathryn M. Lewis, Mark Lathrop, Rudolf Uher, Katrina Pirlo, Daniel Souery, Mandy Y.M. Ng, Joanna Hauser, Tina Zagar, Thomas G. Schulze, Anne Farmer, Ole Mors, Erik Roj Larsen, Ian W. Craig, Katherine J. Aitchison, Anna Placentino, Nader Perroud, Marcella Rietschel, Piotr M. Czerski, Borut Jerman, Amy W. Butler, Sarah Cohen-Woods, Michael R. Barnes, Peter McGuffin, Wolfgang Maier, Gerome Breen, Pierandrea Muglia, and Astrid Zobel
- Subjects
Antidepressive Agents/*therapeutic use ,Interleukin-11/genetics ,Genome-wide association study ,Bioinformatics ,ddc:616.89 ,0302 clinical medicine ,Nortriptyline/therapeutic use ,Genome-Wide Association Study ,Copy-number variation ,Pharmacogenetics/methods ,Interleukin-6/genetics ,Oligonucleotide Array Sequence Analysis ,Genetics ,Polymorphism, Single Nucleotide/genetics ,Interleukin-11 ,Antidepressive Agents ,3. Good health ,antidepressant response ,GENDEP ,Psychiatry and Mental health ,Phenotype ,Treatment Outcome ,Antidepressive Agents, Second-Generation/therapeutic use ,Antidepressive Agents, Second-Generation ,Sulfotransferases ,medicine.drug ,Genotype ,Nortriptyline ,Citalopram ,Sulfotransferases/genetics ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Depressive Disorder/*drug therapy/genetics ,medicine ,Humans ,Escitalopram ,Citalopram/therapeutic use ,Genotyping ,Genetic association ,Psychiatric Status Rating Scales ,Depressive Disorder ,Depressive Disorder, Major ,Depressive Disorder, Major/drug therapy/genetics ,Interleukin-6 ,business.industry ,030227 psychiatry ,Pharmacogenetics ,business ,030217 neurology & neurosurgery - Abstract
Udgivelsesdato: 2010-May 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.
- Published
- 2010