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Identifying the Common Genetic Basis of Antidepressant Response

Pain O 1 , Hodgson K 1 , Trubetskoy V 2 , Ripke S 2 , Marshe VS 3 , Adams MJ 4 Show all authors , Byrne EM 5 , Campos AI 6 , Carrillo-Roa T 7 , Cattaneo A 8 , Als TD 9 , Souery D 10 , Dernovsek MZ 11 , Fabbri C 1 , Hayward C 12 , Henigsberg N 13 , Hauser J 14 , Kennedy JL 15 , Lenze EJ 16 , Lewis G 17 , Müller DJ 3 , Martin NG 6 , Mulsant BH 18 , Mors O 19 , Perroud N 20 , Porteous DJ 21 , Rentería ME 6 , Reynolds CF 22 , Rietschel M 23 , Uher R 24 , Wigmore EM 4 , Maier W 25 , Wray NR 5 , Aitchison KJ 26 , Arolt V 27 , Baune BT 27 , Biernacka JM 28 , Bondolfi G 20 , Domschke K 29 , Kato M 30 , Li QS 31 , Liu YL 32 , Serretti A 33 , Tsai SJ 34 , Turecki G 35 , Weinshilboum R 36 , GSRD Consortium , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium , McIntosh AM 4 , Lewis CM 1

Affiliations 

  • 1 Social, Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom
  • 2 Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Medical Psychology, Berlin, Germany
  • 3 Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 4 Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
  • 5 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
  • 6 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 7 Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
  • 8 Biological Psychiatry Laboratory, IRCCS Fatebenefratelli, Brescia, Italy
  • 9 Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, Denmark
  • 10 Laboratoire de Psychologie Medicale, Université Libre de Bruxelles, Brussels, Belgium
  • 11 University Psychiatric Clinic, University of Ljubliana, Ljubljana, Slovakia
  • 12 MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom
  • 13 Department of Psychiatry, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia
  • 14 Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland
  • 15 Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 16 Healthy Mind Lab, Washington University School of Medicine in St. Louis, St. Louis, Missouri
  • 17 Division of Psychiatry, University College London, London, United Kingdom
  • 18 Division of Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 19 Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
  • 20 Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland
  • 21 Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
  • 22 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 23 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Heidelberg University Faculty of Medicine in Mannheim, Mannheim, Germany
  • 24 Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
  • 25 Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
  • 26 Department of Psychiatry, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
  • 27 Department of Psychiatry, University of Münster, Münster, Germany
  • 28 Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota
  • 29 Department of Psychiatry and Psychotherapy, Medical Center, University of Freiburg, Freiburg, Germany
  • 30 Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan
  • 31 Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, New Jersey
  • 32 Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taipei, Taiwan
  • 33 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
  • 34 Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
  • 35 Department of Psychiatry, Douglas Institute, McGill University, Montreal, Quebec, Canada
  • 36 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
Biol Psychiatry Glob Open Sci, 2022 Apr;2(2):115-126.
PMID: 35712048 DOI: 10.1016/j.bpsgos.2021.07.008

Abstract

BACKGROUND: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.

METHODS: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.

RESULTS: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.

CONCLUSIONS: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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