A Genome-Wide Association Study Reveals Loci Influencing Height and Other Conformation Traits in Horses

Abstract

The molecular analysis of genes influencing human height has been notoriously difficult. Genome-wide association studies (GWAS) for height in humans based on tens of thousands to hundreds of thousands of samples so far revealed ∼200 loci for human height explaining only 20% of the heritability. In domestic animals isolated populations with a greatly reduced genetic heterogeneity facilitate a more efficient analysis of complex traits. We performed a genome-wide association study on 1,077 Franches-Montagnes (FM) horses using ∼40,000 SNPs. Our study revealed two QTL for height at withers on chromosomes 3 and 9. The association signal on chromosome 3 is close to the LCORL/NCAPG genes. The association signal on chromosome 9 is close to the ZFAT gene. Both loci have already been shown to influence height in humans. Interestingly, there are very large intergenic regions at the association signals. The two detected QTL together explain ∼18.2% of the heritable variation of height in horses. However, another large fraction of the variance for height in horses results from ECA 1 (11.0%), although the association analysis did not reveal significantly associated SNPs on this chromosome. The QTL region on ECA 3 associated with height at withers was also significantly associated with wither height, conformation of legs, ventral border of mandible, correctness of gaits, and expression of the head. The region on ECA 9 associated with height at withers was also associated with wither height, length of croup and length of back. In addition to these two QTL regions on ECA 3 and ECA 9 we detected another QTL on ECA 6 for correctness of gaits. Our study highlights the value of domestic animal populations for the genetic analysis of complex traits.

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

“…LCORL-NCAPG are, together with HMGA2, two of the loci that are most consistently associated with stature and body size variation across multiple studies and species. The LCORL-NCAP region has previously been associated with body size in human, cattle, dog, pig, and horse (Gudbjartsson et al 2008;Pryce et al 2011;Vaysse et al 2011;Rubin et al 2012;Signer-Hasler et al 2012;Tetens et al 2013;Sahana et al 2015). Our results are consistent with a selective sweep at the LCORL-NCAP region related to selection for increased size in domestic rabbits, since all normal-sized rabbits included in this study are significantly larger than wild rabbits and were fixed for a single haplotype ( Figure 4B).…”

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

“…Relatively few loci influencing morphological traits are also observed in dogs (14,60) and can be attributed to typically small founder populations and selective breeding (23,45), resulting in longer LD compared with humans and the subsequent use of fewer individuals for association studies (23,45,46). Additional markers genotyped in this study suggest the causative polymorphism may lie downstream of the SNP BIEC2_808543 and within the LCORL coding sequence and is not likely the BIEC2-808543 SNP as proposed by Makvandi-Nejad et al (37) and Signer-Hasler et al (56). Presence of a 5 kb retrogene copy of the 3=-LCORL coding sequence on ECA 9 may complicate future identification of causal variants.…”

“…The overall goal for this study was to identify and map morphological features unique to TWH that are permissive for alternate performance traits in the TWH. The primary locus controlling body size in the TWH is the same ECA3 LCORL/NCAPG region previously identified in other breeds of horse (37,41,56,62). Relatively few loci influencing morphological traits are also observed in dogs (14,60) and can be attributed to typically small founder populations and selective breeding (23,45), resulting in longer LD compared with humans and the subsequent use of fewer individuals for association studies (23,45,46).…”

“…Isolated mouse homologs, Mlr1 and Mlr2, were identified as transcription factors with Mlr1 predominantly expressed in spermatocytes of the testis and suggesting a role in spermatogenesis (31). The LCORL/NCAPG genes have already been identified in other association studies for height in humans, cattle, and horses (13,30,32,34,37,41,43,48,56,58,62,63,66). In humans and horses no causative mutation in the coding sequence of LCORL or NCAPG has been identified (13,56).…”

“…Only loci on ECA3 surpassed our Bonferroni cut-off, including a 4 bp indel we identified within an intron near the 3=-end of LCORL. Three markers on ECA3 span a 0.38 Mb region that encompasses the previously reported LCORL/NCAPG genes (37,41,56). Two of these SNPs are located ϳ100 Kb upstream from the LCORL/ NCAPG genes (Fig.…”