TY - JOUR
T1 - Assessing thyroid cancer risk using polygenic risk scores
AU - Liyanarachchi, Sandya
AU - Gudmundsson, Julius
AU - Ferkingstad, Egil
AU - He, Huiling
AU - Jonasson, Jon G
AU - Tragante, Vinicius
AU - Asselbergs, Folkert W
AU - Xu, Li
AU - Kiemeney, Lambertus A
AU - Netea-Maier, Romana T
AU - Mayordomo, Jose I
AU - Plantinga, Theo S
AU - Hjartarson, Hannes
AU - Hrafnkelsson, Jon
AU - Sturgis, Erich M
AU - Brock, Pamela
AU - Nabhan, Fadi
AU - Thorleifsson, Gudmar
AU - Ringel, Matthew D
AU - Stefansson, Kari
AU - de la Chapelle, Albert
N1 - 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.
PY - 2020/3/17
Y1 - 2020/3/17
N2 - 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.
AB - 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.
KW - Adult
KW - Biomarkers, Tumor/genetics
KW - Case-Control Studies
KW - Cohort Studies
KW - DNA Mutational Analysis
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Iceland/epidemiology
KW - Male
KW - Middle Aged
KW - Models, Genetic
KW - Multifactorial Inheritance
KW - Penetrance
KW - Polymorphism, Single Nucleotide
KW - Predictive Value of Tests
KW - ROC Curve
KW - Risk Assessment/methods
KW - Risk Factors
KW - Thyroid Cancer, Papillary/epidemiology
KW - Thyroid Gland/pathology
KW - Thyroid Neoplasms/epidemiology
KW - United Kingdom/epidemiology
KW - United States/epidemiology
KW - Polygenic risk score
KW - GWAS
KW - Risk prediction
KW - Thyroid cancer
UR - http://www.scopus.com/inward/record.url?scp=85081735431&partnerID=8YFLogxK
U2 - 10.1073/pnas.1919976117
DO - 10.1073/pnas.1919976117
M3 - Article
C2 - 32132206
SN - 0027-8424
VL - 117
SP - 5997
EP - 6002
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -