01675-A: A Validation Study of Whole Genome Association Analyses for Canine Cryptorchidism in Siberian Huskies
Grant Status: Closed
Grant Amount: $12,960
Dr. Max F. Rothschild, PhD, Iowa State University
June 1, 2011 - May 31, 2012
Sponsor(s): Siberian Husky Club of America
Breed(s): Siberian Husky
Project Summary Cryptorchidism, or hidden testicles is one of the common congenital problems in dogs. This condition may lead to testicular cancer and infertility. Therefore, elimination of this problem in breeding population would help future offspring. Some evidence exists that this trait is controlled by multiple genes. The earliest candidate gene approach in our lab found that collagen type II, alpha I (COL2A1) was associated with cryptorchidism in Siberian Huskies. A whole genome association study (WGAS) with over 170,000 genetic differences called SNPs (Single Nucleotide Polymorphisms) using 149 male Siberian Huskies (78 affected and 71 normal) identified the associations of SNPs located within or close to chromosomal regions containing genes on chromosomes 1 and X. This earlier study strongly suggests the involvement of two or more genes for canine cryptorchidism, and it also promotes a novel hypothesis about an interaction of the genes located on chromosomes X and 1. Although our earlier WGAS results are exciting, any WGAS for a multiple gene controlled trait needs to be validated with additional dogs to increase its power.
Therefore, the present study initially carried out a similar WGAS approach on another sample of 55 male Siberian Husky dogs to validate the previously identified results for canine cryptorchidism. The results from this replication study showed associations with cryptorchidism on chromosome 6 rather than chromosome X and 1. This observation provided a clue that the cryptorchidism associated chromosomal regions may vary for individual sample populations. Hence we combined the genotypes of the current data set of 55 male dogs with our previous data set of 149 Siberian Huskies and an additional dog to understand the different subpopulations and the associated chromosomal regions for cryptorchidism in those subpopulations. Two subpopulations were identified by using clustering software�s. A total of 140 (67 affected and 73 normal) Siberian Husky male dogs constitute subpopulation 1 and those were collected mostly from USA and Canada. Subpopulation 2 had a total of 65 (39 affected and 26 unaffected) Siberian Husky male dogs, which were collected mostly from UK. Association analyses using individual genotypes and their combinations called haplotypes were performed in three stages for these subpopulations separately. The computational programs called PLINK, Gensel and Blossoc were used in different stages of analyses. The results at different stages provided some clues that chromosomal regions containing extracellular matrix regulating genes on X chromosome additional to the other chromosomes might have some contribution to canine cryptorchidism. But none of these analyses in the current study can conclude specific chromosomal regions that are significantly associated with canine cryptorchidism since the sample size is small in each subpopulation.
Hence, a larger population may be needed to obtain a clearer picture and a higher level of significance for the identified regions in the present study and to design an effective genetic test for canine cryptorchidism in the future. Additionally, sequencing of all dog chromosomes from affected and normal dogs may also be helpful to explore the genetic cause for cryptorchidism in Siberian Huskies.