PO.PS01.07 · 人群科学
在前瞻性队列中刻画癌症多基因风险评分:考量PRS方法构建、诊断年龄、遗传血统与样本重叠
Characterizing polygenic risk scores for cancer in prospective cohorts: Considering PRS method construction, age of diagnosis, genetic ancestry, and sample overlap
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摘要 Abstract
中文摘要
成熟的前瞻性癌症队列为研究多基因风险评分(PRS)与非遗传因素联合用于个体化疾病风险预测提供了独特机会。然而,其应用效果可能因队列特异性特征而有所差异。我们比较了四种PRS加权策略:PRS-CSx、Lassosum、边缘汇总统计量的多族裔联合分析(mJAM)前向选择程序,以及标准全基因组关联研究(GWAS)衍生权重,在八个大型前瞻性队列中进行了评估,共计超过一百万受试者,来自多族裔队列(MEC,n=73,139)、老龄化遗传流行病学研究(GERA,n=103,358)、妇女健康倡议(WHI,n=46,794)、护士健康研究I(NHS,n=20,195)和II(NHS2,n=16,082)、卫生专业人员随访研究(HPFS,n=12,649)、英国生物样本库(UKB,n=474,775)以及All of Us(AoU,n=317,956)。
这些队列共同构成了一个独特多样化的研究人群,涵盖多个种族与族裔群体、广泛的年龄分布,以及与发现GWAS人群既有重叠又有非重叠的样本。我们在所有加权方法和情境下评估了四种主要癌症(乳腺癌、前列腺癌、结直肠癌和肺癌)的PRS表现。我们的研究结果表明,PRS构建方法的选择与目标队列的特征均对疾病风险的刻画产生实质性影响。
通过在八个大型且多样化的前瞻性队列中整合四种不同的PRS方法,本研究提供了迄今为止关于情境依赖性变异最全面的评估之一,并为正在进行的、结合遗传与非遗传因素的风险预测模型的开发提供了指导。
查看英文原文 English abstract
Well-established prospective cancer cohorts provide a unique opportunity to investigate the combined use of polygenic risk scores (PRSs) and non-genetic factors for personalized disease risk prediction. However, their application can vary depending on cohort-specific characteristics. We compared four PRS weighting strategies: PRS-CSx, Lassosum, a multi-ethnic joint analysis of marginal summary statistics (mJAM) forward selection procedure, and standard genome-wide association study (GWAS) derived weights, across eight large, prospective cohorts, totaling over a million subjects from the Multiethnic Cohort (MEC, n=73,139), the Genetic Epidemiology Research on Aging (GERA, n=103,358), the Women's Health Initiative (WHI, n=46,794), the Nurses' Health Studies I (NHS, n=20,195) and II (NHS2, n=16,082), the Health Professionals Follow-up Study (HPFS, n=12,649), the UK Biobank (UKB, n=474,775) and All of Us (AoU, n=317,956).
Together, these cohorts represent a uniquely diverse study population spanning multiple racial and ethnic groups, broad age distributions, and both overlapping and non-overlapping samples with discovery GWAS populations. We evaluated PRS performance for four major cancers (breast, prostate, colorectal, and lung) across all weighting methods and contexts. Our findings show that both the choice of PRS construction method and the characteristics of the target cohort substantially influence the characterization of disease risk.
By integrating four distinct PRS approaches across eight large and diverse prospective cohorts, this study provides one of the most comprehensive evaluations to date of context-dependent variation and provides guidance for ongoing development of risk prediction models that combine genetic and non-genetic factors.
利益披露 Disclosure
J. Dias, None..
G. King, None..
D. Bogumil, None..
B. Huang, None..
F. Chen, None..
D. V. Conti, None.