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

View ORCID ProfileChiara Fabbri, Katherine E. Tansey, Roy H. Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Lee Sang-Hyuk, Stephen Newhouse, Hamel Patel, Michel Guipponi, Nader Perroud, Guido Bondolfi, Micheal O’Donovan, Glyn Lewis, Joanna M. Biernacka, Richard M. Weinshilboum, Anne Farmer, Katherine J. Aitchison, Ian Craig, Peter McGuffin, Rudolf Uher, Cathryn M. Lewis
doi: https://doi.org/10.1101/109827
Chiara Fabbri
1 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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  • ORCID record for Chiara Fabbri
Katherine E. Tansey
3 College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
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Roy H. Perlis
4 Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, USA
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Joanna Hauser
5 Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
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Neven Henigsberg
6 Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia
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Wolfgang Maier
7 Department of Psychiatry, University of Bonn, Bonn, Germany
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Ole Mors
8 Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
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Anna Placentino
9 Biological Psychiatry Unit and Dual Diagnosis Ward, Istituto Di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy
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Marcella Rietschel
10 Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
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Daniel Souery
11 Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel—Centre Européen de Psychologie Médicale, Brussels, Belgium
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Gerome Breen
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Charles Curtis
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Lee Sang-Hyuk
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Stephen Newhouse
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Hamel Patel
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Michel Guipponi
12 Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland
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Nader Perroud
13 Department of Psychiatry, University of Geneva, Geneva, Switzerland
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Guido Bondolfi
13 Department of Psychiatry, University of Geneva, Geneva, Switzerland
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Micheal O’Donovan
14 MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Glyn Lewis
15 School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
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Joanna M. Biernacka
16 Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, United States
17 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
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Richard M. Weinshilboum
18 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
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Anne Farmer
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Katherine J. Aitchison
19 Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
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Ian Craig
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Peter McGuffin
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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Rudolf Uher
20 Department of Psychiatry, Dalhousie University, Halifax, Canada
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Cathryn M. Lewis
2 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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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 SNP, gene and pathway level. Coverage of genetic variants was increased compared to 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. NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) served for replication.

7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology 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), while 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, no convincing replication was achieved. Further studies may help in clarifying their role.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 20, 2017.
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New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation
Chiara Fabbri, Katherine E. Tansey, Roy H. Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Lee Sang-Hyuk, Stephen Newhouse, Hamel Patel, Michel Guipponi, Nader Perroud, Guido Bondolfi, Micheal O’Donovan, Glyn Lewis, Joanna M. Biernacka, Richard M. Weinshilboum, Anne Farmer, Katherine J. Aitchison, Ian Craig, Peter McGuffin, Rudolf Uher, Cathryn M. Lewis
bioRxiv 109827; doi: https://doi.org/10.1101/109827
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New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation
Chiara Fabbri, Katherine E. Tansey, Roy H. Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Lee Sang-Hyuk, Stephen Newhouse, Hamel Patel, Michel Guipponi, Nader Perroud, Guido Bondolfi, Micheal O’Donovan, Glyn Lewis, Joanna M. Biernacka, Richard M. Weinshilboum, Anne Farmer, Katherine J. Aitchison, Ian Craig, Peter McGuffin, Rudolf Uher, Cathryn M. Lewis
bioRxiv 109827; doi: https://doi.org/10.1101/109827

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