Efficient and accurate framework for genome-wide gene-environment interaction analysis in large-scale biobanks

作者：Yuzhuo Ma, Yanlong Zhao, Ji‐Feng Zhang, Wenjian Bi · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-57887-3 · 被引用次数：8 · 研究领域：Genetic Associations and Epidemiology、Genetic Mapping and Diversity in Plants and Animals、Gene expression and cancer classification

Gene-environment interaction (G×E) analysis elucidates the interplay between genetic and environmental factors. Genome-wide association studies (GWAS) have expanded to encompass complex traits like time-to-event and ordinal traits, which provide richer phenotypic information. However, most existing scalable approaches focus only on quantitative or binary traits. Here we propose SPAGxECCT, a scalable and accurate framework for diverse trait types. SPAGxECCT fits a genotype-independent model and employs a hybrid strategy including saddlepoint approximation (SPA) for accurate p value calculation, especially for low-frequency variants and unbalanced phenotypic distributions. We extend SPAGxECCT to SPAGxEmixCCT, which accounts for population stratification and is applicable to multi-ancestry or admixed populations. SPAGxEmixCCT can further be extended to SPAGxEmixCCT-local, which identifies ancestry-specific G×E effects using local ancestry. Through extensive simulations and real data analyses of UK Biobank data, we demonstrate that SPAGxECCT and SPAGxEmixCCT are scalable to analyze large-scale study cohort, control type I error rates effectively, and maintain power. Here, the authors introduce a statistical framework for analyzing gene-environment interactions across diverse traits, effectively addressing ancestry differences while maintaining scalability for largescale genome-wide studies.