Leveraging Joint-Specific Phenotypes for Genome-Wide Association Studies and SNP Heritability Estimation of Equine Osteochondrosis and Fetlock Osteochondral Fragments

Background Equine osteochondrosis (OC) and fetlock osteochondral fragments are highly prevalent developmental joint disorders caused by failure of the growing skeleton, often leading to intra-articular fragments that require arthroscopic surgery and impose substantial economic and animal welfare burdens. To reduce prevalence, phenotype-based selection has had limited success, prompting interest in genomic approaches. Progress in genetic research has been hindered by difficulties in assembling large study populations, inconsistent phenotype definitions, and the disease’s dynamic nature. This study aimed to perform joint-specific case–control genome‐wide association studies (GWAS) and estimate single nucleotide polymorphism (SNP) based heritabilities for OC and fetlock osteochondral fragments in horses. Seven base phenotypes with two to four levels of strictness were defined using a novel semi-quantitative scoring system and paired with high-density genotypes. Results Across 23 GWAS on 716 horses, 214 suggestive SNPs were identified, including 50 that reached genome-wide significance. Based on predefined criteria, eight genomic regions of interest were identified, revealing 11 novel candidate genes: LDB2 for total OC; SCUBE3 , MAPK13 and MAPK14 for hock OC; and FGF6 , FGF23 , IL17A , IL17F , TRAM2 , BMP5 , and PPP2R5C for palmaro-/plantaroproximal osteochondral fragments of the proximal phalanx (POF). No candidate genes were detected for distal intermediate ridge of the tibia (DIRT) OC. For stifle OC, fetlock OC, and dorsoproximal fragments of the proximal phalanx (DOF), suggestive SNPs did not define genomic regions of interest. SNP-based heritability estimates ranged from 26.2–27.1% for total OC; 53.9–61.0% for hock OC; 49.4–61.2% for DIRT OC; 1.5–14.2% for stifle OC; 0.0-13.7% for fetlock OC; 10.0-54.8% for POF; and 5.7–39.6% for DOF. Conclusion This study represents the first GWAS on DOF in horses and identifies novel candidate genes involved in angiogenesis and bone development for total OC, hock OC and POF. The results demonstrate the importance of stringent, joint-specific phenotypes, as even minor differences in phenotype definition substantially affected heritability estimates and the detection of genomic associations and candidate genes. The high heritability of hock and DIRT OC indicates considerable potential for rapid genetic improvement, compared to the lower heritability observed for total OC, fetlock OC, and stifle OC.