Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia
By D. Curtis. 2018
125 citations recorded by the source corpus.
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. Aims To explore the distribution of the schizophrenia PRS in subjects of different ancestry. Method 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 eleven 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 ten times as high as the mean difference between European schizophrenia cases and controls. The distributions of scores for African and European subjects hardly overlapped. Conclusions 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 for 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 and raising issues of inequity. Previous studies which have used the PRS should be re-examined in the light of these findings. Declaration of interest The author declares he has no conflict of interest.
Subfields: Genetics, Psychiatry and Mental health
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In Genetics
- John P. A. Ioannidis
- Alicia R. Martin
- Mark J. Daly
- Gary S. Collins
- Karel G. M. Moons
- Matti Pirinen
- Chris Wallace
- Tal Yarkoni
In Psychiatry and Mental health
Citations in the corpus
- The Missing Diversity in Human Genetic Studies. (2019, unknown): “For instance, a UK study of PRS for schizophrenia showed a 10-fold higher score in Africans and African-Americans than in Europeans, but this does not reflect true disease risk, indicating that the PRS was not informative across populations (Curtis, 2018).”
- Machine learning and artificial intelligence research for patient benefit: 20 critical questions on transparency, replicability, ethics, and effectiveness (2020, background): “68 The issue of data that are not truly representative of the entire target population is particularly important, 69 because it highlights the importance of fairness considerations at every point in the project cycle.”
- Geographic variation and bias in polygenic scores of complex diseases and traits in Finland (2018, background): “Earlier, results of phenotypically inconsistent PS differences between continental groups have been reported (Martin et al. 2017; Reisberg et al. 2017; Curtis 2018).”