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

Introduction: Both genes and environment are associated with weight-related outcomes, but it remains unclear to which extent environmental factors are consistently associated with weight-related outcomes 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 studies using polygenic indices for BMI. Six electronic databases (APA PsycArticles, APA PsycInfo, ERIC, MEDLINE, Psychology and Behavioral Sciences Collection, SocINDEX) were searched. Peer-reviewed empirical studies using polygenic indices for BMI and examining environmental exposures and weight-related outcomes were included.Results: A total of 1,104 effects from 84 studies were included: 148 for main genetic effects, 275 for associations between environmental factors and weight-related outcomes controlling for a polygenic index for BMI, and 681 for gene-environment interactions. Higher genetic predisposition for BMI was positively associated with BMI for all ancestry groups, with evidence of gene-environment interplay.Conclusions: This meta-analysis highlights the importance of both genetic and environmental factors in explaining individual variation in weight-related outcomes. Most studies did not account for gene-environment correlation confounding, and most focused on populations of European ancestry. Future research should prioritize methodologies that address bias and focus on underrepresented ancestry groups to improve inclusivity.