Gene mapping of monogenic disorders and complex diseases via genome wide association studies

Inherited rickets, lower motor neuron disease and chondrodysplasia were recently reported genetic disorders that had been identified on sheep farms in New Zealand. Animals with rickets showed softening and weakening bone, and were characterized by decreased growth rate, thoracic lordosis and angular limb deformities. Sheep diagnosed with lower motor neuron disease were characterized by poor muscle tone and progressive weakness from about one week of age, leading to severe tetraparesis, recumbency and muscle atrophy. Chondrodysplasia in Texel sheep was characterized by dwarfism and angular deformities of the forelimbs. These three disorders were determined likely simple autosomal recessive by backcross breeding trials. One complex disease called cryptorchidism was found with high prevalence in Siberian Husky dogs. This disease is a congenital disorder characterized by failure of one or both testicles to descend into the scrotum. In order to map gene loci and thus the mutations involved, genome wide association studies were conducted using the Illumina OvineSNP50 BeadChip for the three monogenic disorders and the Illumina CanineHD BeadChip for cryptorchidism. Several mapping strategies were utilized including homozygosity mapping, Bayesian inference, case-control analysis and these were followed by fine mapping with a candidate gene approach.;In results, a nonsense mutation 250C > T in exon 6 of the dentin matrix protein 1 gene (DMP1) was revealed as the putative cause of inherited rickets in Corriedale sheep. The missense mutation c.2909G > C on exon 21 of the ATP/GTP-binding protein 1 gene (AGTPBP1) was identified likely being responsible for lower motor neuron disease in Romney sheep. A 1-bp deletion (g.25513delT) on exon 3 in the solute carrier family 13, member 1 gene (SLC13A1) was discovered for chondrodysplasia seen in Texel sheep. The 100% concordant rate of genotypes for mutations in certain sheep populations with the recessive pattern of inheritance for the three disorders indicates a causative relationship between these mutations with their related monogenic disorders. Gene knockout mice and studies of similar diseases in humans provide more evidence to support this conclusion. In the cryptorchidism study, the anti-mullerian hormone type II receptor gene (AMHR2) was found located in a 1Mb window on dog chromosome CFA27 which is associated with cryptorchidism using a BayesB approach in a subgroup of Siberian Husky dogs. Previous human studies support AMHR2 is a very promising functional candidate gene for the development of cryptorchidism. In conclusions, we have successfully identified putative causative mutations responsible for the three monogenic disorders in sheep, and also found a promising candidate gene in a putative region associated with cryptorchidism in dogs. Our finding could shed light on further investigations of the role of involved genes and the affected animals could be used as animal models for human diseases with similar mechanisms.