Abstract
Congenital idiopathic megaesophagus (CIM) is a gastrointestinal disorder of dogs wherein the esophagus is dilated and swallowing activity is reduced, causing regurgitation of ingesta. Affected individuals experience weight loss and malnourishment and are at risk for aspiration pneumonia, intussusception, and euthanasia. Great Danes have among the highest incidences of CIM across dog breeds, suggesting a genetic predisposition. We generated low-pass sequencing data for 83 Great Danes and used variant calls to impute missing whole genome single-nucleotide variants (SNVs) for each individual based on haplotypes phased from 624 high-coverage dog genomes, including 21 Great Danes. We validated the utility of our imputed data set for genome-wide association studies (GWASs) by mapping loci known to underlie coat phenotypes with simple and complex inheritance patterns. We conducted a GWAS for CIM with 2,010,300 SNVs, identifying a novel locus on canine chromosome 1 (P-val = 2.76 × 10−10). Associated SNVs are intergenic or intronic and are found in two clusters across a 1.7-Mb region. Inspection of coding regions in high-coverage genomes from affected Great Danes did not reveal candidate causal variants, suggesting that regulatory variants underlie CIM. Further studies are necessary to assess the role of these non-coding variants.
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Acknowledgements
The authors wish to thank the dog owners who contributed to this study and the Upright Canine Brigade for help recruiting participants.
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This project was supported by the American Kennel Club Canine Health Foundation (#02709 to LAC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the views of the Foundation. This work was also supported by the Great Dane Club of America Charitable Trust (LAC).
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LAC, KLT, and SGF conceptualized the study; SMB and KLT recruited the study cohort; SGF created the reference panel and performed the imputation, SMB, EAG, JME, and LAC performed data analysis; LAC and JME wrote the manuscript; EAG prepared the figures. All authors reviewed the manuscript.
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Supplementary Figure 1 Principal component analysis for the CIM GWAS cohort. Principal components (PC) 1 and 2 are plotted for 83 Great Danes (TIF 8936 KB)
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Bell, S.M., Evans, J.M., Greif, E.A. et al. GWAS using low-pass whole genome sequence reveals a novel locus in canine congenital idiopathic megaesophagus. Mamm Genome 34, 464–472 (2023). https://doi.org/10.1007/s00335-023-09991-2
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DOI: https://doi.org/10.1007/s00335-023-09991-2