Despite the implementation of enhanced management practices, chronic wasting disease (CWD) in U.S. white-tailed deer (Odocoileus virginianus; hereafter WTD) continues to expand geographically. Herein, we perform the largest genome-wide association analysis (GWAA) to date for CWD (n = 412 CWD-positive; n = 758 CWD-non-detect) using a custom Affymetrix Axiom® single nucleotide polymorphism (SNP) array (n = 121,010 SNPs), and confirm that differential susceptibility to CWD is a highly heritable (h² = 0.611 ± 0.056) polygenic trait in farmed U.S. WTD, but with greater trait complexity than previously appreciated. We also confirm PRNP codon 96 (G96S) as having the largest effects on risk (P ≤ 3.19E-08; Phenotypic Variance Explained ≥ 0.025) across three U.S. regions (Northeast, Midwest, South). However, 20 CWD-positive WTD possessing codon 96SS genotypes were also observed, including one that was lymph node and obex positive. Beyond PRNP, we also detected 23 significant SNPs (P-value ≤ 5E-05) implicating ≥ 24 positional candidate genes; many of which have been directly implicated in Parkinson’s, Alzheimer’s, and prion diseases. Genotype-by-environment (GxE) interaction GWAA revealed a SNP in the lysosomal enzyme gene ARSB as having the most significant regional heterogeneity of effects on CWD (P ≤ 3.20E-06); with increasing copy number of the minor allele increasing susceptibility to CWD in the Northeast and Midwest; but with opposite effects in the South. In addition to ARSB, 38 significant GxE SNPs (P-value ≤ 5E-05) were also detected, thereby implicating ≥ 36 positional candidate genes; the majority of which have also been associated with aspects of Parkinson’s, Alzheimer’s, and prion diseases.

Additional File (AF) 1-29 are detailed summary results and outputs from EMMAX GWAA, EMMAX GxE GWAA, and METAL meta-analysis. Table S1 and Table S2 are supplementary Tables. See ReadMe File.