UC Davis

Lameness imposes concerns for dairy cattle welfare and farmer profitability. After mastitis, lameness is the second most prevalent disease in dairy cattle and is commonly caused by digital dermatitis (DD, also known as foot warts), sole ulcers (SU), and white line disease (WLD). Digital dermatitis is an infectious foot lesion, whereas SU and WLD are noninfectious lesions that arise due to compromised horn production. Genomic selection against these foot lesions and its potential impact on other health traits (mastitis, hypocalcemia, displaced abomasum, ketosis, and metritis) requires the identification of loci associated with these foot lesions and assessment of the genetic correlation of foot lesions with other health traits. To detect susceptibility loci, a genome-wide association study (GWAS) was performed using genotypes from the high density SNP array (777K SNPs) and case/control phenotypes for DD (controls n =129, DD n = 85), SU (controls n = 102, SU n = 152), WLD (controls = 102, WLD n = 117), SU and/or WLD (SU and WLD, controls n = 102, n = 198), and any type of noninfectious foot lesion (controls n = 102, cases = 217). GWAS was performed using linear mixed model (LMM) and random forest (RF) approaches, and effect sizes of top SNPs were estimated using Bayesian regression. For the LMM GWAS, the number of effective SNPs (NES) was calculated as the number of SNPs that were not in linkage disequilibrium and used as the denominator to define Bonferroni-corrected p-value thresholds of genome-wide statistical significance (p ≤ 0.05/NES) and suggestive significance (p ≤ 0.2/NES). Genetic correlation among foot lesions and health traits was estimated using bivariate genome-based restricted maximum likelihood (GREML) analysis, and a multi-trait GWAS was conducted to identify genomic regions contributing to genetic correlation. Top SNPs identified in the GWAS were in or near genes that were functionally relevant to foot lesion etiology. For DD, both the LMM and RF analyses identified regions of association on Bos taurus autosome (BTA) 1 and 2, with one of the regions on BTA2 containing candidate genes related to immune function. The LMM GWAS revealed an associated region on BTA 8 for SU and BTA13 for WLD, SU and WLD, and noninfectious foot lesions. These associated regions contained genes related to wound healing, skin lesions, bone growth and mineralization, adipose tissue, and keratinization. Furthermore, the region on BTA8 included a SNP previously associated with SU susceptibility. The RF GWAS for SU, WLD, SU and WLD, and noninfectious lesions were overfitted, suggesting that the SNP effects were very small and prevented detection of susceptibility loci using this approach. Estimated effect sizes of top SNPs were small, and though significant genetic correlation was detected among lameness and health traits, the sample size prevented detection of loci contributing to multiple traits. The small effect sizes and the limited ability to detect pleiotropic loci reinforces that the environment plays a nontrivial role in disease susceptibility, and the remaining genetic component is likely governed by many loci. Larger sample sizes are necessary to identify small effect loci and their association with individual or multiple lameness and health traits amidst a strong environmental effect.