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Assessing thyroid cancer risk using polygenic risk scores

Assessing thyroid cancer risk using polygenic risk scores


Title: Assessing thyroid cancer risk using polygenic risk scores
Author: Liyanarachchi, Sandya
Gudmundsson, Julius   orcid.org/0000-0003-2517-4763
Ferkingstad, Egil   orcid.org/0000-0001-8090-7988
He, Huiling
Jónasson, Jón Gunnlaugur
Tragante, Vinicius
Asselbergs, Folkert W.
Xu, Li
Kiemeney, Lambertus A.
Netea-Maier, Romana T.
... 11 more authors Show all authors
Date: 2020-03-17
Language: English
Scope: 6
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Cancer Center
Series: Proceedings of the National Academy of Sciences of the United States of America; 117(11)
ISSN: 0027-8424
DOI: https://doi.org/10.1073/pnas.1919976117
Subject: GWAS; Polygenic risk score; Risk prediction; Thyroid cancer; Skjaldkirtill; Krabbamein; Multidisciplinary
URI: https://hdl.handle.net/20.500.11815/3357

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Citation:

Liyanarachchi , S , Gudmundsson , J , Ferkingstad , E , He , H , Jónasson , J G , Tragante , V , Asselbergs , F W , Xu , L , Kiemeney , L A , Netea-Maier , R T , Mayordomo , J I , Plantinga , T S , Hjartarson , H , Hrafnkelsson , J , Sturgis , E M , Brock , P , Nabhan , F , Thorleifsson , G , Ringel , M D , Stefansson , K & de la Chapelle , A 2020 , ' Assessing thyroid cancer risk using polygenic risk scores ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 117 , no. 11 , pp. 5997-6002 . https://doi.org/10.1073/pnas.1919976117

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 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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Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.

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