title: Toward the most ideal case-control design with related and unrelated dogs in whole-exome sequencing studies.
abstract: With the recent development of whole-exome sequencing enrichment designs for the dog, a novel tool for disease-association studies became available. The aim of disease-association studies is to identify one or a very limited number of putative causal variants or genes from the large pool of genetic variation. To maximize the efficiency of these studies and to provide some directions of what to expect, we evaluated the effect on variant reduction for various combinations of cases and controls for both dominant and recessive types of inheritance assuming variable degrees of penetrance and detectance. In this study, variant data of 14 dogs (13 Labrador Retrievers and one Dogue de Bordeaux), obtained by whole-exome sequencing, were analyzed. In the filtering process, we found that unrelated dogs from the same breed share up to 70% of their variants, which is likely a consequence of the breeding history of the dog. For the designs tested with unrelated dogs, combining two cases and two controls gave the best result. These results were improved further by adding closely related dogs. Reduced penetrance and/or detectance has a drastic effect on the efficiency and is likely to have a profound effect on the sample size needed to elucidate the causal variant. Overall, we demonstrated that sequencing a small number of dogs results in a marked reduction of variants that are likely sufficient to pinpoint causal variants or genes.
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000, Ghent, Belgium.
authors.forename: B J G
authors.initials: BJ
authors.lastname: Broeckx
authors.affiliation: Department of Applied Biosciences, University College Ghent, 9000, Ghent, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Coopman
authors.affiliation: Department of Medical Imaging and Small Animal Orthopaedics, Ghent University, 9820, Merelbeke, Belgium.
authors.forename: G E C
authors.initials: GE
authors.lastname: Verhoeven
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000, Ghent, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: De Keulenaer
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000, Ghent, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: De Meester
authors.affiliation: Department of Medicine and Clinical Biology of Small Animals, Ghent University, 9820, Merelbeke, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Bavegems
authors.affiliation: Department of Medicine and Clinical Biology of Small Animals, Ghent University, 9820, Merelbeke, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Smets
authors.affiliation: Department of Medical Imaging and Small Animal Orthopaedics, Ghent University, 9820, Merelbeke, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Van Ryssen
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000, Ghent, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Van Nieuwerburgh
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000, Ghent, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Deforce
mesh_terms: D000818:Animals; D001947:Breeding; D016022:Case-Control Studies; D004285:Dogs / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D040582:Inheritance Patterns; D008297:Male; D010375:Pedigree; D019683:Penetrance; D012107:Research Design; D018401:Sample Size
keywords: canine; design of experiments; disease-association studies; targeted sequencing; variant filtering