Discovery and characterization of gene-by-environment and epistatic genetic effects in a vertebrate model

Phenotypic variation arises from interactions between genetic and environmental factors, but disentangling these effects for complex traits remains challenging in observational cohorts like human biobanks. Model organisms with controlled genetic and environmental variation complement human studies in analyzing higher-order effects such as gene-by-environment (G×E) interactions, dominance, and epistasis. We utilized 76 medaka strains from the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel to compare heart rate plasticity across temperatures. An F2 segregation analysis identified 16 quantitative trait loci (QTLs), many exhibiting dominance, G×E, G×G, and G×G×E interactions. We experimentally validated four candidate genes, revealing temperature-sensitive heart rate effects. Finally, we simulated how genome-wide association study (GWAS) discovery power depends on statistical model choice. Our results suggest that the limited detection of non-additive effects in human GWASs stems from current study designs and sample sizes. This work demonstrates the value of controlled model organism studies for dissecting complex trait genetics and informing association study design.