Gene-environment interplay explaining individual variation in weight-related outcomes: A systematic review and meta-analysis of studies using polygenic indices

Introduction: Genetic and environmental factors are both associated with weight-related outcomes, but it remains unclear to what extent environmental exposures are consistently associated beyond genetic predisposition, and to what extent they modify genetic risk. Methods: We meta-analyzed evidence on gene-environment interplay and individual variation in weight-related outcomes, focusing on peer-reviewed studies examining environmental exposures and using polygenic indices for BMI. Six electronic databases (APA PsycArticles, APA PsycInfo, ERIC, MEDLINE, Psychology and Behavioral Sciences Collection, SocINDEX) were searched.Results: The meta-analysis included 1,161 estimates from 88 studies: 153 estimates of main genetic associations, 283 of associations between environmental factors and weight-related outcomes controlling for a polygenic index for BMI, and 725 of gene-environment interactions (G×E). Higher genetic predisposition for BMI was positively associated with BMI for all ancestry groups. The overall association between environmental exposures and BMI, controlling for genetic risk, was r=.12 (p<.001) for both European and combined ancestry groups. Overall G×E effects ranged from r=.06 to .12 depending on ancestry group and whether imputed effect sizes were included. Moderator analyses showed no significant differences in effect sizes across different exposure categories.Conclusions: This meta-analysis highlights the importance of both genetic and environmental factors in explaining variation in weight-related outcomes. Most studies did not account for gene-environment correlation confounding and focused primarily on European ancestry populations. Future research should prioritize methodologies that address bias and focus on underrepresented ancestry groups to improve inclusivity.