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Original Investigation
January 13, 2021

Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status

Author Affiliations
  • 1Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark
  • 2National Centre for Register-Based Research (NCRR), Aarhus University, Aarhus, Denmark
  • 3Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark
  • 4Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark
  • 5Center for Genomics and Personalized Medicine, Aarhus University, Aarhus, Denmark
  • 6Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona
  • 7Institute of Biological Psychiatry, Mental Health Center Sct Hans, Roskilde, Denmark
  • 8Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
  • 9Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
  • 10Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
  • 11Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia
  • 12Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia
  • 13Psychosis Research Unit, Aarhus University Hospital–Psychiatry, Aarhus, Denmark
  • 14Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 15Center for GeoGenetic, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
  • 16Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
JAMA Psychiatry. Published online January 13, 2021. doi:10.1001/jamapsychiatry.2020.4172
Key Points

Question  How well does the depression polygenic risk score (PRS) in combination with parental psychosocial factors determine the absolute risk of depression before the age of 30 years?

Findings  In this case-cohort study of 17 098 patients with depression, the absolute risk of depression by the age of 30 years differed substantially depending on an individual’s combination of risk factors, ranging from 1.0% among male individuals with high socioeconomic status in the bottom 2% of the PRS distribution to 23.7% among female individuals in the top 2% of PRS with a parental history of psychiatric disorders.

Meaning  The PRS was not superior to other factors but was useful in conjunction with other risk factors.

Abstract

Importance  Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk.

Objective  To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression.

Design, Setting, and Participants  This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs.

Exposures  The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses).

Main Outcomes and Measures  Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings.

Results  Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual’s combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders.

Conclusions and Relevance  This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.

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