A Contextual Polygenic Adaptation Framework for Human Genetic Variation

Despite major advances in genome-wide association studies (GWAS), much of the heritable variation underlying complex human traits remains poorly explained, particularly across diverse populations. Classical models of human genetic variation emphasize additive effects of loci, demographic history, and selection, yet increasingly fail to capture the context-dependent and network-based nature of polygenic traits. Here, we propose a novel theoretical framework— Contextual Polygenic Adaptation (CPA)—which conceptualizes human complex traits as emergent properties of multilocus genetic networks whose phenotypic effects are dynamically modulated by environmental, regulatory, and population-specific contexts. By integrating evidence from systems genetics, gene–environment interaction studies, and global population genomics, CPA offers a unifying explanation for observed disparities in polygenic prediction accuracy and adaptive trait variation across ancestries. Key Words : Genome-wide association studies (GWAS), heritable genetic variation, complex human traits, polygenic traits, additive genetic effects, demographic history, natural selection, multilocus genetic networks, context-dependent effects, Contextual Polygenic Adaptation (CPA), gene–environment interactions, systems genetics, global population genomics, polygenic prediction, phenotypic variation, population and ancestry differences