Sonehara Kyuto, Okada Yukinori
Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
Cancer Sci. 2025 Feb;116(2):288-296. doi: 10.1111/cas.16402. Epub 2024 Nov 19.
Genome-wide association studies (GWAS) statistically assess the association between tens of millions of genetic variants in the whole genome and a phenotype of interest. Genome-wide association studies enable the elucidation of polygenic inheritance of cancer, in which myriad low-penetrance genetic variants collectively contribute to a substantial proportion of the heritable susceptibility. In addition to the robust genotype-phenotype associations provided by GWAS, combining GWAS data with functional genomic datasets or sophisticated statistical genetic methods unlocks deeper insights. Integrating genotype and molecular phenotyping data facilitates functional characterization of GWAS association signals through molecular quantitative trait loci mapping and transcriptome-wide association studies. Furthermore, aggregating genome-wide polygenic signals, including subthreshold associations, enables one to estimate genetic correlations across diverse phenotypes and helps in clinical risk predictions by evaluating polygenic risk scores. In this review, we begin by summarizing the rationale for GWAS of cancer, introduce recent methodological updates in the GWAS-derived downstream analyses, and demonstrate their applications to GWAS of cancers.
全基因组关联研究(GWAS)通过统计学方法评估全基因组中数以千万计的遗传变异与感兴趣的表型之间的关联。全基因组关联研究有助于阐明癌症的多基因遗传,其中无数低 penetrance 遗传变异共同构成了相当比例的遗传易感性。除了 GWAS 提供的强大基因型-表型关联外,将 GWAS 数据与功能基因组数据集或复杂的统计遗传方法相结合,可以获得更深入的见解。整合基因型和分子表型数据有助于通过分子数量性状位点定位和全转录组关联研究对 GWAS 关联信号进行功能表征。此外,汇总全基因组多基因信号,包括亚阈值关联,能够估计不同表型之间的遗传相关性,并通过评估多基因风险评分帮助进行临床风险预测。在本综述中,我们首先总结癌症 GWAS 的基本原理,介绍 GWAS 衍生的下游分析中最近的方法更新,并展示它们在癌症 GWAS 中的应用。