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Common wheat (Triticum aestivum) is a hexaploid crop comprising three diploid sub-genomes labeled A, B, and D. The objective of this study is to investigate whether there is a discernible influence pattern from the D sub-genome with epistasis in genomic models for wheat diseases. Four genomic statistical models were employed; two models considered the linear genomic relationship of the lines. The first model (G) utilized all molecular markers, while the second model (ABD) utilized three matrices representing the A, B, and D sub-genomes. The remaining two models incorporated epistasis, one (GI) using all markers and the other (ABDI) considering markers in sub-genomes A, B, and D, including inter- and intra-sub-genome interactions. The data utilized pertained to three diseases: tan spot (TS), septoria nodorum blotch (SNB), and spot blotch (SB), for synthetic hexaploid wheat (SHW) lines. The results (variance components) indicate that epistasis makes a substantial contribution to explaining genomic variation, accounting for approximately 50% in SNB and SB and only 29% for TS. In this contribution of epistasis, the influence of intra- and inter-sub-genome interactions of the D sub-genome is crucial, being close to 50% in TS and higher in SNB (60%) and SB (60%). This increase in explaining genomic variation is reflected in an enhancement of predictive ability from the G model (additive) to the ABDI model (additive and epistasis) by 9%, 5%, and 1% for SNB, SB, and TS, respectively. These results, in line with other studies, underscore the significance of the D sub-genome in disease traits and suggest a potential application to be explored in the future regarding the selection of parental crosses based on sub-genomes.