Genome-Wide Pharmacogenetics of Antidepressant Response in the GENDEP Project

R Uher, N Perroud, M. Y. M Ng, J Hauser, N Henigsberg, W Maier, O Mors, A Placentino, M Rietschel, D Souery, T Zagar, P. M Czerski, B Jerman, E. R Larsen, T. G Schulze, A Zobel, S Cohen Woods, K Pirlo, A. W Butler, P Muglia, M. R Barnes, M Lathrop<, A Farmer, G Breen, K. J Aitchison, I Craig, C. M Lewis and P. McGuffin

American Journal of Psychiatry, 2010, 167(5), 555-564. DOI: 10.1176/appi.ajp.2009.09070932

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.

ASCI-ID: 1364-192