Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia: A Danish Population-Based Study and Meta-analysis
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IMPORTANCE: Schizophrenia has a complex etiology influenced both by genetic and nongenetic factors but disentangling these factors is difficult. OBJECTIVE: To estimate (1) how strongly the risk for schizophrenia relates to the mutual effect of the polygenic risk score, parental socioeconomic status, and family history of psychiatric disorders; (2) the fraction of cases that could be prevented if no one was exposed to these factors; (3) whether family background interacts with an individual's genetic liability so that specific subgroups are particularly risk prone; and (4) to what extent a proband's genetic makeup mediates the risk associated with familial background. DESIGN, SETTINGS, AND PARTICIPANTS: We conducted a nested case-control study based on Danish population-based registers. The study consisted of 866 patients diagnosed as having schizophrenia between January 1, 1994, and December 31, 2006, and 871 matched control individuals. Genome-wide data and family psychiatric and socioeconomic background information were obtained from neonatal biobanks and national registers. Results from a separate meta-analysis (34,600 cases and 45,968 control individuals) were applied to calculate polygenic risk scores. EXPOSURES: Polygenic risk scores, parental socioeconomic status, and family psychiatric history. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs), attributable risks, liability R2 values, and proportions mediated. RESULTS: Schizophrenia was associated with the polygenic risk score (OR, 8.01; 95% CI, 4.53-14.16 for highest vs lowest decile), socioeconomic status (OR, 8.10; 95% CI, 3.24-20.3 for 6 vs no exposures), and a history of schizophrenia/psychoses (OR, 4.18; 95% CI, 2.57-6.79). The R2 values were 3.4% (95% CI, 2.1-4.6) for the polygenic risk score, 3.1% (95% CI, 1.9-4.3) for parental socioeconomic status, and 3.4% (95% CI, 2.1-4.6) for family history. Socioeconomic status and psychiatric history accounted for 45.8% (95% CI, 36.1-55.5) and 25.8% (95% CI, 21.2-30.5) of cases, respectively. There was an interaction between the polygenic risk score and family history (P = .03). A total of 17.4% (95% CI, 9.1-26.6) of the effect associated with family history of schizophrenia/psychoses was mediated through the polygenic risk score. CONCLUSIONS AND RELEVANCE: Schizophrenia was associated with the polygenic risk score, family psychiatric history, and socioeconomic status. Our study demonstrated that family history of schizophrenia/psychoses is partly mediated through the individual's genetic liability.
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Patients suffering from psychotic disorders were overrepresented in this cohort.
“Patients suffering from psychotic disorders were overrepresented here, similar to studies of homeless or precariously housed people worldwide. 3,41-43”
From The Hotel Study—Clinical and Health Service Effectiveness in a Cohort of Homeless or Marginally Housed Persons (2017) · cites this paper as [43]
The Results describe a Danish schizophrenia case-control sample, not a cohort of homeless or precariously housed people. Searches for homelessness, housing, and overrepresentation found no passage in our copy addressing whether psychotic disorders are overrepresented in such cohorts (page numbers unavailable). (LLM, conf=0.77)
Experimental — accuracy not yet measuredOnly 17.4% of the association between family history of psychosis and the disorder is mediated through a modelled polygenic risk score.
“However, only 17.4% of the association between family history of psychosis and the disorder is mediated through a modelled polygenic risk score 131 .”
From Preventive psychiatry: a blueprint for improving the mental health of young people (2021) · cites this paper as [131]
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- Authors
- Agerbo, E., Sullivan, P. F., Vilhjálmsson, B. J., Pedersen, C. B., Mors, O., Børglum, A. D., Hougaard, D. M., Hollegaard, M. V., Meier, S., Mattheisen, M., Ripke, S., Wray, N. R., & Mortensen, P. B.
- Affiliations
- Aarhus University (DK)
- University of North Carolina at Chapel Hill (US)
- Aarhus University Hospital (DK)
- Statens Serum Institut (DK)
- Lundbeck Foundation (DK)
- Broad Institute (US)
- The University of Queensland (AU)
- Corresponding author
- Agerbo, Esben
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2015-07-01
- Volume
- 72
- Issue
- 7
- Pages
- 635
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2002788019
- Cited by
- 319
- References
- 31
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 17 · 2023: 57 · 2022: 31 · 2021: 39 · 2020: 26 · 2019: 40 · 2018: 22 · 2017: 22 · 2016: 24 · 2015: 6
- FWCI
- 20.04
- Type
- journal article
- Language
- en
- Open access
- green
- pure.au.dk
- Licence
- other-oa
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Aarhus Universitet
- Lundbeckfonden (R155-2014-1724)
- H. Lundbeck A/S
- Medical Research Council
- National Health and Medical Research Council (613602, 1047956)
- Strategic Research Council
- FP7 Ideas: European Research Council (294838)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
- Keywords
- schizophrenia, polygenic risk score, parental socioeconomic status, family history of mental illness, genetic susceptibility, gene-environment interaction, attributable risk, mediation analysis, schizophrenia prevention, psychosis, genetic risk prediction, genome-wide association data, socioeconomic status, schizophrenia risk factors
- MeSH terms
- Bipolar Disorder, Denmark, Family, Female, Humans, Male, Parents, Psychotic Disorders, Risk Factors, Schizophrenia, Social Class, Odds Ratio, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Genetic Association Studies
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