Large scale across-breed genome-wide association study reveals a variant in HMGA2 associated with inguinal cryptorchidism risk in dogs

Abstract

Cryptorchidism is the most common congenital sex development disorder in dogs. Despite this, little progress has been made in understanding its genetic background. Extensive genetic testing of dogs through consumer and veterinary channels using a high-density SNP genotyping microarray coupled with links to clinical records presents the opportunity for a large-scale genome-wide association study to elucidate the molecular risk factors associated with cryptorchidism in dogs. Using an inter-breed genome-wide association study approach, a significant statistical association on canine chromosome 10 was identified, with the top SNP pinpointing a variant of HMGA2 previously associated with adult weight variance. In further analysis we show that incidence of cryptorchidism is skewed towards smaller dogs in concordance with the identified variant's previous association with adult weight. This study represents the first putative variant to be associated with cryptorchidism in dogs.

Fig 1. Inguinal cryptorchidism GWAS.

(A) GWAS of 3736 inguinal cryptorchidism cases versus 3736 male controls. (B) GWAS of 3736 inguinal cryptorchidism cases versus 3736 genetically matched male controls to further correct for population substructure.

Fig 2. The complex genetic structure of the study sample set.

(A) PCA showing the diversity of breed and non-breed individuals included in the study. (B) PCA plot showing the set of 3736 matched cases and controls.

Fig 3

(A) Box plot representing the weight distribution of cases and genetically matched controls over the age of 1.5 years. The mean weight of cases (962) was 13.11Kg, compared with a mean weight for controls (3727) of 15.74kg (p = 1.198 x 10⁻⁹). (B) Box plot representing the weight distribution of HMGA2 wt/wt cases and genetically-matched HMGA2 wt/wt controls over the age of 1.5 years. The mean weight of cases (356) was 25.53kg, compared with a mean weight for controls (1718) of 26.63kg (p = 0.101).