Genetic approaches to Brachycephalic Obstructive Airway Syndrome in three canine breeds.

Presenter David Sargan
Authors Lajos Kalmar(1), Nai-Chieh Liu(1), Cathryn Mellersh(2), Jane Ladlow(1), David Sargan(1)
Affiliations 1. Dept of Veterinary Medicine, University of Cambridge, 2 . The Animal Health Trust, Newmarket
Presentation Type Talk


Introduction: Brachycephalic obstructive airway syndrome (BOAS) is a serious health and welfare problem for many brachycephalic dogs, and is beyond any doubt the most divisive issue within companion animal medicine in the UK at the present time. Whilst the genetics of brachycephaly have been investigated elsewhere, the genetics of BOAS have received less attention: in part because brachycephaly is by definition a primary condition for BOAS and has been the focus of previous genetic studies; in part because the measurement of BOAS has been subjective, relying on auscultation and the veterinarian’s interpretation of what is normal, whilst the phenotype shows a gradation in severity which makes analysis of affected status as a binary trait problematic; and in part because the phenotype is progressive, of moderately late onset and there are large environmental factors, including temperature, humidity, fitness and body condition of the dog.

We have partly overcome these difficulties by developing accurate and objective techniques for looking at the breathing cycle at rest using whole body barometric plethysmography, and comparing parameters within the breathing cycles with respiratory performance measured by auscultation before and after an exercise test designed to put the animal in slight respiratory deficit. This work, which is published, has shown high predictive ability for exercise tolerance from the respiratory trace at rest, and has allowed us to assess the contribution of skull conformation to the disease, the effectiveness of different surgeries etc.. Prevalence of severe disease in our animals was about 17% in pugs and 15% in each of French Bulldogs and Bulldogs.

We have also started looking for genes involved in the disease in these three breeds. A GWAS has been performed using DNA from 182 pugs, 210 FBs and 172 BDs and analysed using PLINK and EMMAX software. Heritability in our cohorts measured using Genome Wide Complex Trait Analysis varied from over 40% to under 60%. After permutation, even the best supported SNP in each breed only just reached genome wide significance, but several loci in each breed did show suggestive significance (P value outside the 95% confidence interval of the Q/Q plot). The disease associated loci were different in each breed. Whole genome sequencing of control and affected animals failed to show non-conservative amino acid changes in coding sequences, but several potentially significant changes in sequence were detected. Studies on a second cohort are now underway. The possible use of a genomic estimated breeding value to assist in breeding these dogs away from BOAS, whilst retaining as much as possible of current head shape, is supported by the predictive value of these loci in estimating exercise tolerance test grade.