Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro

Wenmin Zhang (), Robert Sladek, Yue Li, Hamed Najafabadi and Josée Dupuis ()
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Wenmin Zhang: McGill University
Robert Sladek: McGill University
Yue Li: McGill University
Hamed Najafabadi: McGill University
Josée Dupuis: McGill University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Classical gene-by-environment interaction (GxE) analysis can be used to characterize genetic effect heterogeneity but has a high multiple testing burden in the context of genome-wide association studies (GWAS). We adapt a colocalization method, SharePro, to account for effect heterogeneity in fine-mapping and identify candidates for GxE analysis with reduced multiple testing burden. SharePro demonstrates improved power for both fine-mapping and GxE analysis compared to existing methods as well as well-controlled false type I error in simulations. Using smoking status stratified GWAS summary statistics, we identify genetic effects on lung function modulated by smoking status that are not identified by existing methods. Additionally, using sex stratified GWAS summary statistics, we characterize sex differentiated genetic effects on fat distribution. In summary, we have developed an analytical framework to account for effect heterogeneity in fine-mapping and subsequently improve power for GxE analysis. The SharePro software for GxE analysis is openly available at https://github.com/zhwm/SharePro_gxe .

Date: 2024
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DOI: 10.1038/s41467-024-53818-w

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