Genome-wide polygenic risk scores predict risk of glioma and molecular subtypes.

Autor:	Nakase T; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA., Guerra GA; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA., Ostrom QT; Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA., Ge T; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Psychiatry, Center for Precision Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Melin BS; Department of Diagnostics and Intervention, Oncology Umeå University, Umeå, Sweden., Wrensch M; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA., Wiencke JK; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA., Jenkins RB; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Eckel-Passow JE; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., Bondy ML; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA., Francis SS; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.; Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA., Kachuri L; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Oct 03; Vol. 26 (10), pp. 1933-1944.
DOI:	10.1093/neuonc/noae112
Abstrakt:	Background: Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data. Methods: We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P < 5 × 10-8). PRS models were trained using GWAS stratified by histological (10 346 cases and 14 687 controls) and molecular subtype (2632 cases and 2445 controls), and validated in 2 independent cohorts. Results: PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range = 11-30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (SD) (OR = 1.93, P = 2.0 × 10-54 vs. OR = 1.83, P = 9.4 × 10-50) and higher explained variance (R2 = 2.82% vs. R2 = 2.56%). Individuals in the 80th percentile of the PRS-CS distribution had a significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P = 2.4 × 10-12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC = 0.839 vs. AUC = 0.895, PΔAUC = 6.8 × 10-9). Conclusions: Genome-wide PRS has the potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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