Genotype by environment interactions for chronic wasting disease in farmed U.S. white-tailed deer

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.