Gene-environment interaction loci with signatures of mid- to late Holocene selection show evidence for diet-dependent genetic effects

Environmental change is a major driver of adaptation, yet most evolutionary studies assume that genetic effects remain constant across environments. Recent biobank-scale studies have identified widespread gene-environment interactions (GxE), but their contribution to recent human evolution remains unclear. Here, we combined genome-wide GxE maps with allele-frequency trajectories spanning the last ~10,000 years to test whether environmentally responsive variants contributed to recent human adaptation. Among 45 independent loci, three showed significant signatures of directional selection. These loci, associated with urate, LDL-C and cholesterol levels, showed parallel frequency increases and overlapping acceleration points around 4,700-7,200 years ago. Selection-associated GxE loci were enriched for urate-related variants and for interactions involving meat and cheese consumption. Diet-associated variants showed a consistent interaction direction across loci. Notably, across candidate traits, GxE variants were enriched among significant GWAS loci with selection signatures. Furthermore, analyses across worldwide populations revealed broadly shared derived allele frequency increases and comparable temporal patterns. Taken together, our results suggest that gene-environment interactions present an important and previously underappreciated component of recent human evolution.