The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple inheritance pattern. To understand their inheritance, we analysed the melanoma grade, grey level, vitiligo grade, and speckling grade of 1,119 Grey horses (7,146 measurements) measured in six countries over a 9-year period. We estimated narrow sense heritability (h2), and we decomposed this parameter into polygenic heritability (h2POLY), heritability due to the Grey (STX17) mutation (h2STX17), and heritability due to agouti (ASIP) locus (h2ASIP). A high heritability was found for greying (h2 = 0.79), vitiligo (h2 = 0.63), and speckling (h2 = 0.66), while a moderate heritability was estimated for melanoma (h2 = 0.37). The additive component of ASIP was significantly different from zero only for melanoma (h2ASIP = 0.02). STX17 controlled large proportions of phenotypic variance (h2STX17 = 0.18–0.55) and overall heritability (h2STX17/h2 = 0.28–0.83) for all traits. Genetic correlations among traits were estimated as moderate to high, primarily due to the effects of the STX17 locus. Nevertheless, the correlation between progressive greying and vitiligo-like depigmentation remained large even after taking into account the effects of STX17. We presented a model where four traits with complex inheritance patterns are strongly influenced by a single mutation. This is in line with evidence of recent studies in domestic animals indicating that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. Furthermore, we demonstrated that the STX17 mutation explains to a large extent the moderate to high genetic correlations among traits, providing an example of strong pleiotropic effects caused by a single gene.
Clarifying the genetic architecture of complex traits is a problem with profound implications for agriculture, biology, and medicine. Using data from Lipizzan horses with the grey coat phenotype, we present an example of a single mutation (intronic duplication in STX17) that explains 18%–55% of phenotypic variation in four complex traits, while polygenic background additive effects also explain 11%–57% of phenotypic variation. This study provides a prime example of complex traits being influenced by genes of moderate-to-large effect and supports further the evidence of recent studies in domestic animals that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. We further show that the STX17 mutation accounts for a large proportion of the estimated genetic correlations between the traits. This case of strong pleiotropic effects of a single mutation on complex traits makes this work of significant general interest for biology and medicine.