An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome
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Abstract
The age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (p<5×10−05) derived from GWAS and 551 heritable traits from the UK Biobank study (N = 334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility. To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.
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Associations between patient-level PGSs and outcomes are more robust, potentially capturing causal associations.
“we and others argue that associations between patient-level PGSs and outcomes are more robust, potentially capturing causal associations.95”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [95]
The Introduction says PRS associations may highlight putative causal relationships and can have higher statistical power than the MR approach it compared. It does not establish that those associations are more robust; its simulations found substantial false-positive rates from horizontal pleiotropy, and it says robust follow-up evaluation is necessary. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBecause inherited sequence variation is a prominent cause of phenotypic variation (but the reverse is not true), risk variants identified by GWAS have value as genetic instruments for mapping causal relationships between traits and inferring contributions of biomarkers and environmental exposures to disease.
“In addition, as inherited sequence variation is a prominent cause of phenotypic variation (but the reverse is not true), risk variants identified by GWAS have value as genetic instruments, mapping causal relationships between traits and inferring contributions made by circulating biomarkers and environmental exposures to disease development66.”
From A brief history of human disease genetics (2020) · cites this paper as [66]
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- Authors
- Richardson, T. G., Harrison, S., Hemani, G., & Davey Smith, G.
- Affiliations
- University of Bristol (GB)
- MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Corresponding author
- Richardson, Tom G
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-03-05
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6400585
- OpenAlex
- W2899836172
- Cited by
- 198
- References
- 48
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 24 · 2023: 14 · 2022: 37 · 2021: 41 · 2020: 44 · 2019: 16
- FWCI
- 20.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (acceptedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Medical Research Council (MC_UU_00011/1)
- Wellcome Trust (208806/Z/17/Z)
- Health Data Research UK (MR/S003886/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- polygenic risk score, phenome-wide association study, schizophrenia, genetic susceptibility, cognitive function, causal relationship, Mendelian randomization, mediation analysis, multivariable Mendelian randomization, complex disease susceptibility, heritable traits, UK Biobank, web application
- MeSH terms
- United Kingdom, Humans, Schizophrenia, Risk Assessment, Genetic Predisposition to Disease, Multifactorial Inheritance, Databases, Genetic, Genome-Wide Association Study
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