Genetic variation associated with Marek’s disease resistance and susceptibility in white leghorn chickens

Despite of effective control by vaccination, Marek's disease virus (MDV) remains a significant threat to poultry health and productivity due to continued virus evolution, which drives the need to better understand host genetic factors underlying the resistance and susceptibility. Although great efforts have been made toward understanding the genetic resistance to MD, the genetic variations underlying varied susceptibility to MD remains poorly understood. In this study, we conducted a comprehensive genome-wide association and pathway enrichment analysis in chicken genomes of a MD-resistant inbred line 6 (LN6), a MD-susceptible inbred line 7 (SUS), and 6 recombinant congenic strains (RCS) derived from the lines 6 and 7. The incidence of MD in the RCS varied significantly, ranging from RCS-J ̶ 0%, RCS-D ̶ 4%, line 6 ̶ 6%, RCS-F ̶ 10%, RCS-W ̶ 15%, RCS-K ̶ 24%, to RCS-M ̶ 41%. The progenital line 7 was observed with a 97% incidence in response to infection with a very virulent plus MDV strain (648A). Three models were constructed: GWAS_LN6 with the line 6 birds contrasted against the remaining birds, GWAS_SUS with the line 7 birds contrasted against the remaining birds, and GWAS_RES-JD6 with group of RCS-J, RCS-D and line 6 together contrasted against the remaining birds. Our results revealed distinct enrichment patterns: while WNT/SHH Axonal Guidance Signaling Pathway is enriched in both GWAS_SUS and GWAS_RES-JD6, the Th2 pathway, Th1/Th2 Activation Pathway, and the interleukin (IL)-33 were predominant in GWAS_SUS. On the other hand, the ISG15 antiviral mechanism and HIPPO signalling pathways were enriched in the GWAS_RES-JD6. In contrast, thyroid cancer signalling, CXCR4, ILK, IL-8, IL-3, JAK/STAT and mTOR signalling pathways were significantly enriched in GWAS_LN6. These findings underscore the complex interplay of immune signalling, host-pathogen interactions, and genetic regulation in shaping MD resistance. Key pathways and candidate genes identified in this study provide valuable targets for further functional validation and may inform future genetic selection and new vaccine strategies to enhance MD resistance in poultry.