https://orcid.org/0000-0002-3078-098X
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Taishi Nakase, Geno A Guerra, Quinn T Ostrom, Tian Ge, Beatrice S Melin, Margaret Wrensch, John K Wiencke, Robert B Jenkins, Jeanette E Eckel-Passow, Glioma International Case-Control Study (GICC), Melissa L Bondy, Stephen S Francis, Linda Kachuri, Genome-wide polygenic risk scores predict risk of glioma and molecular subtypes, Neuro-Oncology, Volume 26, Issue 10, October 2024, Pages 1933–1944, https://doi.org/10.1093/neuonc/noae112
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Abstract
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.
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.
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).
Genome-wide PRS has the potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.
