New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

C Fabbri; K E Tansey; R H Perlis; J Hauser; N Henigsberg; W Maier; O Mors; A Placentino; M Rietschel; D Souery; G Breen; C Curtis; L Sang-Hyuk; S Newhouse; H Patel; M Guipponi; N Perroud; G Bondolfi; M O'Donovan; G Lewis; J M Biernacka; R M Weinshilboum; A Farmer; K J Aitchison; I Craig; P McGuffin; R Uher; C M Lewis

doi:10.1038/tpj.2017.44

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

Pharmacogenomics J. 2018 May 22;18(3):413-421. doi: 10.1038/tpj.2017.44. Epub 2017 Nov 21.

Authors

C Fabbri^{1

2}, K E Tansey³, R H Perlis⁴, J Hauser⁵, N Henigsberg⁶, W Maier⁷, O Mors⁸, A Placentino⁹, M Rietschel¹⁰, D Souery¹¹, G Breen², C Curtis², L Sang-Hyuk², S Newhouse², H Patel², M Guipponi¹², N Perroud¹³, G Bondolfi¹³, M O'Donovan¹⁴, G Lewis¹⁵, J M Biernacka^{16

17}, R M Weinshilboum¹⁸, A Farmer², K J Aitchison¹⁹, I Craig², P McGuffin², R Uher²⁰, C M Lewis²

Affiliations

¹ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
² Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³ College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
⁴ Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, MA, USA.
⁵ Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁶ Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia.
⁷ Department of Psychiatry, University of Bonn, Bonn, Germany.
⁸ Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
⁹ Biological Psychiatry Unit and Dual Diagnosis Ward, Istituto Di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
¹⁰ Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
¹¹ Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel-Centre Européen de Psychologie Médicale, Brussels, Belgium.
¹² Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland.
¹³ Department of Psychiatry, University of Geneva, Geneva, Switzerland.
¹⁴ MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
¹⁵ Division of Psychiatry, University College London (UCL), London, UK.
¹⁶ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
¹⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
¹⁸ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.
²⁰ Department of Psychiatry, Dalhousie University, Halifax, Canada.

Abstract

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

Trial registration: ClinicalTrials.gov NCT00021528.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antidepressive Agents / adverse effects*
Antidepressive Agents / therapeutic use
Depressive Disorder, Major / drug therapy*
Depressive Disorder, Major / genetics
Depressive Disorder, Major / pathology
Genetic Variation
Genome-Wide Association Study*
Genotype
Humans
Integrins / genetics
Nerve Tissue Proteins / genetics
Pharmacogenetics / trends*
Polymorphism, Single Nucleotide
Treatment Outcome

Substances

Antidepressive Agents
ITGA9 protein, human
Integrins
Nerve Tissue Proteins
neurexin IIIalpha

Associated data

ClinicalTrials.gov/NCT00021528

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding