GWAS using low-pass whole genome sequence reveals a novel locus in canine congenital idiopathic megaesophagus

Sarah M. Bell, Jacquelyn M. Evans, Elizabeth A. Greif, Kate L. Tsai, Steven G. Friedenberg, Leigh Anne Clark

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)464-472
Number of pages9
JournalMammalian Genome
Issue number3
StatePublished - Sep 2023

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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