Résumé
Genome-wide association studies (GWAS) have failed to replicate common genetic variants associated with antidepressant response, as defined using a single endpoint. Genetic influences may be discernible by examining individual variation between sustained versus unsustained patterns of response, which may distinguish medication effects from non-specific, or placebo responses to active medication. We conducted a GWAS among 1116 subjects with Major Depressive Disorder from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who were characterized using Growth Mixture Modeling as showing a sustained versus unsustained pattern of clinical response over 12 weeks of treatment with citalopram. Replication analyses examined 585 subjects from the Genome-based Therapeutic Drugs for Depression (GENDEP) trial. The strongest association with sustained as opposed to unsustained response in STAR*D involved a single nucleotide polymorphism (SNP; rs10492002) within the acyl-CoA synthetase short-chain family member 3 gene (ACSS3, p-value=4.5×10-6, odds ratio=0.61). No SNPs met our threshold for genome-wide significance. SNP data were available in GENDEP for 18 of the top 25 SNPs in STAR*D. The most replicable association was with SNP rs7816924 (p=0.008, OR=1.58); no SNP met the replication p-value threshold of 0.003. Joint analysis of these 18 SNPs resulted in the strongest signal coming from rs7816924 (p=2.11×10-7), which resides in chondroitin sulfate N-acetylgalactosaminyltransferase 1 gene (CSGALNACT1). An exploratory genetic pathway analysis revealed evidence for an involvement of the KEGG pathway of long-term potentiation (FDR=02). Results suggest novel genetic associations to sustained response.
| Langue d'origine | English |
|---|---|
| Pages (de-à) | 1157-1165 |
| Nombre de pages | 9 |
| Journal | Journal of Psychiatric Research |
| Volume | 47 |
| Numéro de publication | 9 |
| DOI | |
| Statut de publication | Published - sept. 2013 |
Note bibliographique
Funding Information:Clinical data used in the GWAS were obtained from the limited access datasets distributed from the NIMH-supported “Sequenced Treatment Alternatives to Relieve Depression” (STAR*D) (Contract # N01MH90003 to the University of Texas Southwestern Medical Center). Genotyping of the STAR*D sample was supported by NIMH grant MH072802 to S.P. Hamilton. Analysis of STAR*D clinical data and response trajectories was supported by NIMH grant 1R34MH085933-01 to A.M. Hunter. This manuscript reflects the views of the authors and may not reflect the opinions or views of the STAR*D Study Investigators or the NIH.
Funding Information:
Dr. Cook, over his career, has received research support from Aspect Medical Systems/Covidien, Cyberonics, Eli Lilly and Company, High Q Foundation, John E. Fetzer Foundation, John A. Hartford Foundation, MedAvante, Merck, NARSAD, NIH, Neuronetics, Novartis, Pfizer, Sepracor/Sunovion, Seaside Therapeutics, and the West Coast College of Biological Psychiatry, as Principal Investigator or Co-Investigator. He has served as an advisor or consultant to Allergan, Ascend Media, Bristol-Myers Squibb, Cyberonics, Eli Lilly and Company, Forest Laboratories, Janssen, Neuronetics, NeuroSigma, Pfizer, Scale Venture Partners, and the U.S. Departments of Defense and Justice. He has spoken on behalf of Bristol-Myers Squibb, CME LLC, Eli Lilly & Company, Medical Education Speakers Network, Pfizer, Neuronetics, NeuroSigma, and Wyeth. Dr. Cook's biomedical device patents are assigned to the University of California. He has been granted stock options in NeuroSigma, the licensee of some of his inventions.
Funding Information:
Data for replication analyses were obtained from the GENDEP project which was funded by the European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. H. Lundbeck provided nortriptyline and escitalopram for the GENDEP study. GlaxoSmithKline and the UK National Institute for Health Research of the Department of Health contributed to the funding of the sample collection at the Institute of Psychiatry, London. GENDEP genotyping was funded by a joint grant from the U.K. Medical research council and GlaxoSmithKline ( G0701420 ) and the European Commission Innovative Medicine Initiative Joint Undertaking (IMI-JU) grant n° 115008 . R. Uher is supported by the Canada Research Chairs program ( http://www.chairs-chaires.gc.ca/ ) and the European Commission Innovative Medicine Initiative Joint Undertaking (IMI-JU) grant n° 115008.
Funding Information:
Dr. Uher consults for the World Health Organization and has received research funding from the Canadian Institutes for Health Research, Nova Scotia Health Research Foundation and the European Union. Dr Uher co-chairs a steering board of a research project initiated and funded by Bristol-Myers Squibb and collaborates with a number of pharmaceutical companies as part of the European Union Innovative Medicine Initiative funded NEWMEDS project. Dr Uher has received no personal income from pharmaceutical or biotech industry and holds no equity in companies active in medicine, pharmaceuticals or biotechnology. Dr. Uher has no conflicts of interest in relation to the work presented here.
Funding Information:
Dr. McGrath receives research funding from the NIMH, the State of New York, Roche Laboratories and Forest Pharmaceuticals.
ASJC Scopus Subject Areas
- Psychiatry and Mental health
- Biological Psychiatry
ODD de l’ONU
Cette action contribue à la réalisation des objectifs de développement durable suivants
