Association of polygenic liabilities for major depression, bipolar disorder, and schizophrenia with risk for depression in the Danish population
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Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002). Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.
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Epidemiological surveys have estimated the workplace costs of depression on low work performance while on the job; in the US, the annual salary-equivalent human capital value of these losses has been estimated in the range of $30·1 billion to $51·5 billion.
“Epidemiological surveys have estimated the workplace costs of depression on low work performance while on the job; 232 in the US, the annual salary-equivalent human capital value of these losses has been estimated in the range of $30·1 billion 233 to $51·5 billion. 234”
From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [233]
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- Authors
- Musliner, K. L., Mortensen, P. B., McGrath, J. J., Suppli, N. P., Hougaard, D. M., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Andreassen, O., Pedersen, C. B., Pedersen, M. G., Mors, O., Nordentoft, M., Børglum, A. D., Werge, T., Agerbo, E., & for the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
- Affiliations
- Aarhus University (DK)
- The University of Queensland (AU)
- Copenhagen University Hospital (DK)
- Statens Serum Institut (DK)
- iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Denmark
- Oslo University Hospital (NO)
- Aarhus University Hospital (DK)
- University of Copenhagen (DK)
- Corresponding author
- Musliner, Katherine L.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2019-05-01
- Volume
- 76
- Issue
- 5
- Pages
- 516
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6495355
- OpenAlex
- W2914834617
- Cited by
- 108
- References
- 51
- Citations by year
- 2026: 6 · 2025: 20 · 2024: 10 · 2023: 10 · 2022: 10 · 2021: 23 · 2020: 20 · 2019: 9
- FWCI
- 9.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Worcester Research and Publications (University of Worcester) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Amgen
- Pfizer
- Brigham and Women's Hospital
- Massachusetts General Hospital
- University of Southern California
- Vanderbilt University
- University of Pennsylvania
- University of Minnesota
- State University of New York
- Aarhus Universitet
- Aarhus Universitetshospital
- Johns Hopkins University
- University of Pittsburgh
- Universität Basel
- McGill University
- Rush University
- Norges Teknisk-Naturvitenskapelige Universitet
- Queen Mary University of London
- National University of Ireland
- University of Worcester
- Neuroscience Research Australia
- Vanderbilt University Medical Center
- QIMR Berghofer Medical Research Institute
- Broad Institute
- McGill University Health Centre
- Bundesinstitut für Arzneimittel und Medizinprodukte
- Universitätsmedizin Göttingen
- King's College London
- University College London
- Cardiff University
- University of Aberdeen
- Trinity College Dublin
- Institut National de la Santé et de la Recherche Médicale
- University of New South Wales
- University of Queensland
- Vrije Universiteit Amsterdam
- Eberhard Karls Universität Tübingen
- Technische Universität Dresden
- Dalhousie University
- Lundbeckfonden (R208-2015-3951, R155-2014-1724, R248‐2017‐2003, U01 MH109528)
- University of Toronto
- Universitair Medisch Centrum Utrecht
- Karolinska Institutet
- Westfälische Wilhelms-Universität Münster
- Umeå Universitet
- Universitetet i Bergen
- Universitetet i Oslo
- Háskóli Íslands
- Ludwig-Maximilians-Universität München
- Université Paris Diderot
- Göteborgs Universitet
- Universitat de Barcelona
- Università di Bologna
- Universidad de Granada
- Diakonhjemmet
- Universiteit Antwerpen
- Tartu Ülikool
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Assistance publique-Hôpitaux de Paris
- Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
- Universitat Autònoma de Barcelona
- Universitätsklinikum Köln
- H. Lundbeck A/S
- University of Illinois at Urbana-Champaign
- School of Medicine, Stanford University
- University of California, Los Angeles
- University of North Carolina at Chapel Hill
- University of California, San Diego
- Johns Hopkins Bloomberg School of Public Health
- Veterans Affairs San Diego Healthcare System
- McDonnell Center for Systems Neuroscience
- SUNY Downstate Medical Center
- School of Medicine, Indiana University
- Campbell Family Mental Health Research Institute
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Montreal Neurological Institute and Hospital
- Statens Serum Institut
- National Institute of Mental Health (U01MH109528, U01MH109536, U01 MH1095320, MH1095320)
- NIH Clinical Center
- Janssen Research and Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- polygenic risk score, major depressive disorder, bipolar disorder, schizophrenia, genetic susceptibility, depression risk, age of onset, depression severity, psychosis, first-episode depression, Psychiatric Genomics Consortium, psychiatric hospitalization, Danish population, case-cohort study, depression heterogeneity, treatment setting
- MeSH terms
- Adolescent, Adult, Age Factors, Bipolar Disorder, Child, Denmark, Depression, Major Depressive Disorder, Female, Humans, Male, Risk Factors, Schizophrenia, Linear Models, Proportional Hazards Models, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Young Adult
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