Genetic evaluations and genome-wide association studies for specific digital dermatitis diagnoses in dairy cows considering genotype × housing system interactions.

The present study aimed to use detailed phenotyping for the claw disorder digital dermatitis (DD) considering specific DD stages in 2 housing systems (conventional cubicle barns [CON] and compost-bedded pack barns [CBPB]) to infer possible genotype × housing system interactions. The DD stages included 2,980 observations for the 3 traits DD-sick, DD-acute, and DD-chronic from 1,311 Holstein-Friesian and 399 Fleckvieh-Simmental cows. Selection of the 5 CBPB and 5 CON herds was based on a specific protocol to achieve a high level of herd similarity with regard to climate, feeding, milking system, and location, but with pronounced housing-system differences. Five other farms had a "mixed system" with 2 subherds, one representing CBPB and the other one CON. The CBPB system was represented by 899 cows (1,530 observations), and 811 cows (1,450 observations) represented the CON system. The average disease prevalence was 20.47% for DD-sick, 13.88% for DD-acute, and 5.34% for DD-chronic, with a higher prevalence in CON than in CBPB. After quality control of 50K genotypes, 38,495 SNPs from 926 cows remained for the ongoing genomic analyses. Genetic parameters for DD-sick, DD-acute, and DD-chronic were estimated by applying single-step approaches for single-trait repeatability animal models considering the whole dataset, and separately for the CON and CBPB subsets. Genetic correlations between same DD traits from different housing systems, and between DD-sick, DD-chronic, and DD-acute, were estimated via bivariate animal models. Heritabilities based on the whole dataset were 0.16 for DD-sick, 0.14 for DD-acute, and 0.11 for DD-chronic. A slight increase of heritabilities and genetic variances was observed in CON compared with the "well-being" CBPB system, indicating a stronger genetic differentiation of diseases in a more challenging environment. Genetic correlations between same DD traits recorded in CON or CBPB were close to 0.80, disproving obvious genotype × housing system interactions. Genetic correlations among DD-sick, DD-acute and DD-chronic ranged from 0.58 to 0.81. SNP main effects and SNP × housing system interaction effects were estimated simultaneously via GWAS, considering only the phenotypes from genotyped cows. Ongoing annotations of potential candidate genes focused on chromosomal segments 100 kb upstream and downstream from the significantly associated candidate SNP. GWAS for main effects indicated heterogeneous Manhattan plots especially for DD-acute and DD-chronic, indicating particularities in disease pathogenesis. Nevertheless, a few shared annotated potential candidate genes, that is, METTL25, AFF3, PRKG1, and TENM4 for DD-sick and DD-acute, were identified. These genes have direct or indirect effects on disease resistance or immunology. For the SNP × housing system interaction, the annotated genes ASXL1 and NOL4L on BTA 13 were relevant for DD-sick and DD-acute. Overall, the very similar genetic parameters for the same traits in different environments and negligible genotype × housing system interactions indicate only minor effects on genetic evaluations for DD due to housing-system particularities.

Genomic analyses of claw disorders in Holstein cows: Genetic parameters, trait associations, and genome-wide associations considering interactions of SNP and heat stress.

The aim of the present study was an in-depth genomic analysis to understand the genomic mechanisms of the 3 claw disorders dermatitis digitalis (DD), interdigital hyperplasia (HYP), and sole ulcer (SU). In this regard, we estimated genetic parameters based on genomic relationship matrices, performed genome-wide association studies, annotated potential candidate genes, and inferred genetic associations with breeding goal traits considering the most important chromosomal segments. As a further novelty of this study, we inferred possible SNP × heat stress interactions for claw disorders. The study consisted of 17,264 first-lactation Holstein Friesian cows kept in 50 large-scale contract herds. The disease prevalence was 15.96, 2.36, and 8.20% for DD, HYP, and SU, respectively. The remaining breeding goal traits consisted of type traits of the feet and leg composite, female fertility, health traits, and 305-d production traits. The final genotype data set included 44,474 SNPs from the 17,264 genotyped cows. Heritabilities for DD, HYP, and SU were estimated in linear and threshold models considering the genomic relationship matrix (G matrix). Genetic correlations with breeding goal traits based on G were estimated in a series of bivariate linear models, which were verified via SNP effect correlations for specific chromosome segments (i.e., segments harboring potential candidate genes for DD, HYP, and SU). Genome-wide association studies were performed for all traits in a case-control design by applying a single SNP linear mixed model. Furthermore, for DD, HYP, and SU, we modeled SNP × heat stress interactions in genome-wide association studies. Single nucleotide polymorphism-based heritabilities were 0.04 and 0.08 for DD, 0.03 and 0.10 for SU, and 0.03 and 0.23 for HYP from linear and threshold models, respectively. The genetic correlations between DD, HYP, and SU with conformation traits from the feet and leg composite were positive throughout, indicating the value of indirect selection on conformation traits to improve claw health. Genetic correlations between DD, SU, and HYP with other breeding goal traits indicated impaired female fertility, impaired udder health status, and productivity decline of diseased cows. Genetic correlations among DD, SU, and HYP were moderate to large, indicating that different claw disorders have similar genetic mechanisms. Nevertheless, we identified disease-specific potential candidate genes, and genetic associations based on the surrounding SNPs partly differed from the genetic correlations. Especially for candidate genes contributing to 2 traits simultaneously, correlations based on SNP effects from the respective chromosome segment were close to 1 or to -1. In this regard, we annotated the candidate genes KRT33A and KRT33B for HYP and DD, KIF27 for HYP and calving to first insemination, and MAN1A1 for SU and the production traits. For SNP × heat stress interactions, we identified significant SNPs on BTA 2, 4, 5, 7, 8, 9, 13, 22, 25, and 28, and we annotated the potential candidate genes FSIP2, CLCN1, ADGRV1, DOP1A, THBD, and RHOBTB1. Results indicate gene-specific mechanisms of the claw disorders only in specific environments.