title: A Novel Genome-Wide Association Study Approach Using Genotyping by Exome Sequencing Leads to the Identification of a Primary Open Angle Glaucoma Associated Inversion Disrupting ADAMTS17.
abstract: Closed breeding populations in the dog in conjunction with advances in gene mapping and sequencing techniques facilitate mapping of autosomal recessive diseases and identification of novel disease-causing variants, often using unorthodox experimental designs. In our investigation we demonstrate successful mapping of the locus for primary open angle glaucoma in the Petit Basset Griffon Vendéen dog breed with 12 cases and 12 controls, using a novel genotyping by exome sequencing approach. The resulting genome-wide association signal was followed up by genome sequencing of an individual case, leading to the identification of an inversion with a breakpoint disrupting the ADAMTS17 gene. Genotyping of additional controls and expression analysis provide strong evidence that the inversion is disease causing. Evidence of cryptic splicing resulting in novel exon transcription as a consequence of the inversion in ADAMTS17 is identified through RNAseq experiments. This investigation demonstrates how a novel genotyping by exome sequencing approach can be used to map an autosomal recessive disorder in the dog, with the use of genome sequencing to facilitate identification of a disease-associated variant.
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket Suffolk, CB8 7UU, United Kingdom.
authors.forename: Oliver P
authors.initials: OP
authors.lastname: Forman
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket Suffolk, CB8 7UU, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Pettitt
authors.affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, Veterinary Medical Center, 736 Wilson Road, East Lansing, MI, 48824-1314, United States of America.
authors.forename: András M
authors.initials: AM
authors.lastname: Komáromy
authors.affiliation: Department of Clinical Science & Services, Royal Veterinary College, University of London, Hawkshead Lane, Hatfield, Hertfordshire, AL9 7TA, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Bedford
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket Suffolk, CB8 7UU, United Kingdom.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Mellersh
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000818:Animals; D016022:Case-Control Studies; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005091:Exons; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D008297:Male; D017423:Sequence Analysis, RNA / Q000379:methods*; D057345:Sequence Inversion
chemical_list: D051722:ADAM Proteins