ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 90 citations in OpenAlex.
- Polygenic risk scores in human genetics for study design discovery and translation.Human genetics · 2026Review
- Stratification by a polygenic risk score of common variation aids in Alzheimer's disease rare variant discovery.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Observational
- Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease.American journal of human genetics · 2026Article
- Upregulation of DNA repair-related genes in the prefrontal cortex of patients with schizophrenia with low genetic risk.Schizophrenia (Heidelberg, Germany) · 2026Article
- Polygenic backgrounds influence phenotypic consequences of variants in cells, individuals, and populations.Cell genomics · 2026Review
- Genetic Burden andJournal of personalized medicine · 2026Article
- Individuals whose phenotype deviates from genetic expectation defined by common variation are enriched for rare damaging variants in genes that cause rare disease.medRxiv : the preprint server for health sciences · 2025Article
- Oligogenic risk score for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders.Journal of applied genetics · 2025Article
- Polygenic risk scores in routine genetic diagnostics: what lies ahead?Journal of community genetics · 2025Article
- Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.The Lancet. Respiratory medicine · 2025Observational
- Review
- Emerging Biomarkers for Assessing Thrombotic Risk in Patients Receiving Direct Oral Anticoagulants (DOACs).Cardiovascular & hematological agents in medicinal chemistry · 2025Review
- Polygenic risk and rare variant gene clustering enhance cancer risk stratification for breast and prostate cancers.Communications biology · 2024Article
- Polygenic embryo screening: quo vadis?Journal of assisted reproduction and genetics · 2024Review
- Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know.Current osteoporosis reports · 2024Review
- Genetic modifiers of rare variants in monogenic developmental disorder loci.Nature genetics · 2024Article
- Statistical methods for assessing the effects of de novo variants on birth defects.Human genomics · 2024Review
- Lung cancer in patients who have never smoked - an emerging disease.Nature reviews. Clinical oncology · 2024Review
- Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
purposeIdentifying rare genetic causes of common diseases can improve diagnostic and treatment strategies, but incurs high costs. We tested whether individuals with common disease and low polygenic risk score (PRS) for that disease generated from less expensive genome-wide genotyping data are more likely to carry rare pathogenic variants.
methodsWe identified patients with one of five common complex diseases among 44,550 individuals who underwent exome sequencing in the UK Biobank. We derived PRS for these five diseases, and identified pathogenic rare variant heterozygotes. We tested whether individuals with disease and low PRS were more likely to carry rare pathogenic variants.
resultsWhile rare pathogenic variants conferred, at most, 5.18-fold (95% confidence interval [CI]: 2.32-10.13) increased odds of disease, a standard deviation increase in PRS, at most, increased the odds of disease by 5.25-fold (95% CI: 5.06-5.45). Among diseased patients, a standard deviation decrease in the PRS was associated with, at most, 2.82-fold (95% CI: 1.14-7.46) increased odds of identifying rare variant heterozygotes.
conclusionRare pathogenic variants were more prevalent among affected patients with a low PRS. Therefore, prioritizing individuals for sequencing who have disease but low PRS may increase the yield of sequencing studies to identify rare variant heterozygotes.
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