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

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY

Neuro-oncology Pub Date : 2024-10-03 DOI:10.1093/neuonc/noae112

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, Melissa L Bondy, Stephen S Francis, Linda Kachuri

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引用次数: 0

Abstract

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.

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全基因组多基因风险评分预测胶质瘤风险和分子亚型。

背景：多基因风险评分（PRS多基因风险评分（PRS）综合了许多风险变异的贡献，提供了个性化的遗传易感性特征。由于胶质瘤全基因组关联研究（GWAS）的样本量仍然不大，因此需要利用现有数据有效捕捉遗传风险：方法：我们采用了一种基于连续收缩先验（PRS-CS）的方法来模拟 100 多万个常见变异对疾病风险的联合影响，并将其与只选择达到全基因组显著性（PResults：在各种胶质瘤亚型中，PRS-CS 的预测性普遍高于 PRS-CT，解释方差 (R2) 的中位数增加了 24%（四分位间范围=11-30%）。PRS-CS对胶质母细胞瘤（GBM）的预测效果显著，每标准差的几率比（OR）更大（OR=1.93，P=2.0×10-54 vs. OR=1.83，P=9.4×10-50），解释方差（R2=2.82% vs. R2=2.56%）更高。PRS-CS分布第80百分位数的人与PRS平均值（0.046%，P=2.4×10-12）的人相比，60岁时罹患GBM的风险（0.107%）明显更高。PRS百分位数第95位的人患胶质瘤的终生绝对风险为1.18%，患IDH野生型肿瘤的终生绝对风险为0.76%。当加入人口统计学因素时，PRS-CS增强了病例中IDH突变状态的分类（AUC=0.839 vs. AUC=0.895，PΔAUC=6.8×10-9）：结论：全基因组PRS有望提高高危人群的检测率，并有助于区分预后良好的胶质瘤亚型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.