Assessing thyroid cancer risk using polygenic risk scores
Liyanarachchi, Sandya; Gudmundsson, Julius; Ferkingstad, Egil; He, Huiling; Jonasson, Jon G; Tragante, Vinicius; Asselbergs, Folkert W; Xu, Li; Kiemeney, Lambertus A; Netea-Maier, Romana T; Mayordomo, Jose I; Plantinga, Theo S; Hjartarson, Hannes; Hrafnkelsson, Jon; Sturgis, Erich M; Brock, Pamela; Nabhan, Fadi; Thorleifsson, Gudmar; Ringel, Matthew D; Stefansson, Kari; de la Chapelle, Albert
(2020) Proceedings of the National Academy of Sciences of the United States of America, volume 117, issue 11, pp. 5997 - 6002
(Article)
Abstract
Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results
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to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.
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Keywords: Adult, Biomarkers, Tumor/genetics, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Iceland/epidemiology, Male, Middle Aged, Models, Genetic, Multifactorial Inheritance, Penetrance, Polymorphism, Single Nucleotide, Predictive Value of Tests, ROC Curve, Risk Assessment/methods, Risk Factors, Thyroid Cancer, Papillary/epidemiology, Thyroid Gland/pathology, Thyroid Neoplasms/epidemiology, United Kingdom/epidemiology, United States/epidemiology, Polygenic risk score, GWAS, Risk prediction, Thyroid cancer, General, Multicenter Study, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. We thank Jan Lockman and Barbara Fersch for administrative help. This work was supported by National Cancer Institute Grants P30CA16058 and P01CA124570. Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
(Peer reviewed)