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Dog GWAS Leads to Locus Linked to Digestive Condition in German Shepherds

German Shepherd Dog

NEW YORK – New research suggests that the number of sequence repeats in the "melanin-concentrating hormone receptor 2"-coding gene MCHR2 can inform German shepherd dogs' risk of developing a neuromuscular digestive condition called congenital idiopathic megaesophagus (CIM), which affects swallowing, food movement to the stomach, and survival in puppies.

"By identifying the major genetic contributor to CIM in German shepherd dogs, we have provided breeders with a tool that they can use to reduce disease incidence while preserving genetic diversity," senior author Leigh Anne Clark, a genetics and biochemistry researcher at Clemson University, said in a statement.

For a paper published in PLOS Genetics on Thursday, researchers from Clemson University, the National Human Genome Research Institute, and other centers in the US and UK initially collected blood or buccal swab samples for 530 pet or service dogs with or without CIM, incorporating phenotypic clues for more than 750 additional German shepherds.

In these pooch groups, the team saw that the condition was roughly twice as common in male German shepherds, independent of dog size, pointing to a potential protective effect for female sex. Prior studies have demonstrated that German shepherds are at the most pronounced risk of CIM, though it has also been described in dogs from several other breeds ranging from Great Danes or Labrador retrievers to dachshunds and mini schnauzers.

The investigators went on to perform linkage disequilibrium analyses and a genome-wide association study involving 59 German shepherds with CIM and 53 unaffected control dogs from the same breed, narrowing in on a CIM-related locus on chromosome 12 of the canine genome.

They subsequently assessed that locus in more detail with whole-genome resequencing on three more affected female German shepherd dogs and available genome sequence data for more than 1,300 other domestic dogs, focusing in on a 33-base-pair variable number tandem repeat (VNTR) in MCHR2 that was linked to enhanced CIM risk in the German shepherds.

Using genotyping data for hundreds more CIM-affected or -unaffected dogs, the team profiled allele variants at this locus, before looking at the possibility of predicting CIM based on MCHR2 VNTR genotypes and biological sex.

"Together, sex and the MCHR2 repeat sequence accurately predict affection status in over 75 percent of dogs," the authors reported, "and a genetic test is now available to facilitate breeding decisions aimed at reducing disease incidence."

The team noted that the CIM-related repeat, which falls in MCHR2's first intron, is most often present in two copies in wolves and in other domestic dog breeds compared to the one or three copy alleles identified in most German shepherds.

In the German shepherds, CIM risk was most closely tied to the one-copy repeat allele, the researchers explained, particularly when that allele is present in both copies of the MCHR2 sequence. Because the VNTR spans a T-box transcription factor consensus binding sequence, they speculated that the binding sites may impact the expression of MCHR2 and CIM-related melanin-concentrating hormone activity.

Based on their findings so far, the authors suggested future research efforts may provide still other insights into VNTR and sex-related risk of CIM and other gastrointestinal conditions in German shepherds and other dog breeds.