Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia
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Abstract
BACKGROUND: The polygenic risk score (PRS) for schizophrenia, derived from very large numbers of weakly associated genetic markers, has been repeatedly shown to be robustly associated with schizophrenia in independent samples and also with other diseases and traits. AIM: This study aims to explore the distribution of the schizophrenia PRS in subjects of different ancestry. METHODS: The schizophrenia PRS derived from the large genome-wide association study carried out by the Psychiatric Genetics Consortium was calculated using the downloaded genotypes of HapMap subjects from 11 different ancestral groups. It was also calculated using downloaded genotypes of European schizophrenia cases and controls from the CommonMind Consortium. RESULTS: The PRS for schizophrenia varied significantly between ancestral groups (P<2×10(-16)) and was much higher in African than European HapMap subjects. The mean difference between these groups was 10 times as high as the mean difference between European schizophrenia cases and controls. The distributions of scores for African and European subjects hardly overlapped. CONCLUSION: The PRS cannot be regarded as simply a measure of the polygenic contribution to risk of schizophrenia and clearly contains a strong ancestry component. It is possible that this could be controlled to some extent by incorporating principal components as covariates, but doubts remain as to how it should be interpreted. The PRS derived from European subjects cannot be applied to non-Europeans, limiting its potential usefulness in clinical settings and raising issues of inequity in health provision. Previous studies that have used the PRS should be re-examined in the light of these findings.
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The scientific basis of the imbalance in PRS accuracy has been demonstrated theoretically, in simulations, and empirically across many traits and diseases.
“The scientific basis of this imbalance has been demonstrated theoretically, in simulations, and empirically across many traits and diseases11–22.”
From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [17]
The Results (page not provided) show that the schizophrenia PRS differed markedly between ancestry groups, and the Discussion warns against applying a score derived from European subjects to subjects with African ancestry. This is empirical evidence of an ancestry-related limitation, but the paper does not demonstrate the imbalance theoretically or through simulations, directly compare prediction accuracy, or establish it across many traits and diseases. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPRS are many-fold more accurate in European ancestry individuals than in others, and this disparity is the major ethical and scientific challenge surrounding clinical implementation.
“However, the major ethical and scientific challenge surrounding clinical implementation is that they are many-fold more accurate in European ancestry individuals than others.”
From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [17]
The Discussion (page unavailable) warns that ancestry differences complicate clinical risk prediction and that a PRS derived largely from European samples may not apply to people of African ancestry. It also raises the possibility that non-European populations may be disadvantaged. But its roughly tenfold figure compares differences in PRS values, not predictive accuracy; the paper does not show that PRS are many-fold more accurate in Europeans or rank this as the major implementation challenge. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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- Authors
- Curtis, D.
- Affiliations
- Queen Mary University of London (GB)
- Corresponding author
- Curtis, David
- ORCID
- Curtis, David
- Venue
- Psychiatric Genetics
- Published
- 2018-10
- Volume
- 28
- Issue
- 5
- Pages
- 85-89
- ISSN
- 0955-8829 (ISSN-L)
- OpenAlex
- W2952727348
- Cited by
- 132
- References
- 4
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 15 · 2023: 19 · 2022: 26 · 2021: 12 · 2020: 18 · 2019: 21 · 2018: 4
- FWCI
- 8.41
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Psychiatric Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- University of Pennsylvania
- F. Hoffmann-La Roche (P50MH084053S1, R01MH097276, R01MH093725, R37MH057881, P50M096891, RO1-MH-075916, R01MH085542, P50MH066392, P50MH080405)
- Takeda Pharmaceutical Company
- National Institutes of Health (P50M096891, 5r01mh080405-05, P50MH080405, R37MH057881S1, P50MH084053S1)
- National Institute of Mental Health (R01 MH‐080405, P50MH096891, HHSN271201300031C, R01MH093725, P50MH066392, R01MH075916, R01MH085542, R37MH057881, R01MH097276, P50MH084051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- polygenic risk score, schizophrenia, genetic ancestry, HapMap
- MeSH terms
- Adult, Female, Genotype, Humans, Male, Risk Factors, Schizophrenia, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Databases, Genetic, Black People, White People, Racial Groups, Genome-Wide Association Study
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