Last evening, I participated in a presentation on current Addison’s disease research in Standard Poodles, presented by Steven G. Friedenberg, DVM, PhD, DACVECC, Associate Professor at the University of Minnesota College of Veterinary Medicine. Dr. Friedenberg is both a board-certified veterinary critical care specialist and a geneticist whose research focuses heavily on autoimmune diseases, including Addison’s disease. (College of Veterinary Medicine)

Dogs have two small adrenal glands located near the kidneys. The outer portion, called the adrenal cortex, produces hormones including cortisol and aldosterone. In primary Addison’s disease (hypoadrenocorticism), inadequate adrenal hormone production is responsible for the clinical signs of the disease.

I wanted to share some of the most important information from the presentation with fellow Poodle breeders and owners. This is my summary of the research Dr. Friedenberg presented, with some of the genetics terminology translated into language that is hopefully useful to those of us making real-world decisions about our dogs and breeding programs.

Most Standard Poodle breeders are already well aware that we do not currently have a DNA test for Addison’s. What I found particularly interesting about this presentation was the discussion of why researchers have had such difficulty finding the genetic answer and the new approaches they are now using to look for it.

Why Haven’t Genetic Studies Given Us the Answer?

Researchers have used GWAS, or genome-wide association studies, to investigate Addison’s disease.

A GWAS compares genetic markers across many affected and unaffected dogs, looking for regions of the genome that occur significantly more often in dogs with the disease. If affected dogs consistently share a particular genetic region that unaffected dogs do not, that gives researchers somewhere to investigate further.

But GWAS studies have not produced a simple answer for Addison’s in Standard Poodles.

There are several possible reasons.

1. One is that Addison’s may be a complex or polygenic disease. Polygenic simply means that many genes may be involved, with each contributing only a small amount of risk. Dr. Friedenberg’s laboratory describes its work as focusing on complex/polygenic traits, particularly autoimmune disorders such as Addison’s. (College of Veterinary Medicine)
2. Another possibility is incomplete penetrance. That means a dog can inherit genetic susceptibility without necessarily developing the disease. Genetics may increase risk rather than determine the outcome.
3. There may also be genetic changes that the methods traditionally used for GWAS simply haven’t been very good at detecting.
4. And then there is a particularly interesting possibility for Standard Poodles: some underlying genetic predisposition may already be extremely common within the breed.

Could Part of the Predisposition Be “Fixed” in Standard Poodles?

This was one of the concepts in the presentation that I think is especially important for breeders to understand.

When geneticists say that a genetic variant is “fixed” in a population, they mean it has become present in essentially the entire population.

That does not mean every Standard Poodle is destined to develop Addison’s.

Imagine, for example, that nearly all Standard Poodles carry genetic susceptibility factor “A,” but developing Addison’s requires factor A plus several other genetic or environmental factors.

Researchers conduct a GWAS comparing affected Standard Poodles with unaffected Standard Poodles.

Both groups have factor A.

Factor A therefore doesn’t stand out as being associated with the disease even though it might be an important part of the biological pathway that makes our breed susceptible in the first place.

That could help explain why finding the genetic basis of Addison’s within Standard Poodles has been so difficult.

Researchers Have Also Looked at the Immune System

Addison’s is an immune-mediated disease in which the immune system attacks the adrenal cortex, the outer portion of the adrenal glands. Eventually the glands can no longer produce adequate amounts of critical hormones such as cortisol and aldosterone. (Canine Genetics Lab)

That naturally led researchers to investigate a part of the genome called the Major Histocompatibility Complex, or MHC.

The MHC contains genes that play an important role in how the immune system recognizes and responds to things it encounters.

Dr. Friedenberg used a great analogy in the presentation: a box of crayons.

There is tremendous MHC variation in dogs generally – think of the full box of crayons. But within an individual breed, only a subset of those genetic “colors” may predominate.

Researchers therefore asked a logical question:  Is one particular MHC “color” associated with Addison’s in Standard Poodles?

So far, the answer appears to be no.

In the MHC data presented, no individual haplotype (an inherited combination of genetic variants) showed a statistically significant association with Addison’s in Standard Poodles.

One apparent association found in females did not replicate when investigated in a larger population.

That last point matters. A result becomes much more convincing when researchers can repeat the study in another population and get the same result.

There was, however, another intriguing finding: one MHC “color” is present in more than 80% of Standard Poodles. It may conceivably contribute to susceptibility, but when something is present in almost everyone, it becomes very difficult to prove statistically that it contributes to disease.

Once again, we run into the same problem: researchers may be looking for genetic differences within a population in which some of the important susceptibility factors are already extremely common.

We Now Have a Standard Poodle Reference Genome

This may be one of the most exciting developments presented.

To study a genome, researchers need a reference genome. Think of it as the master map against which other dogs’ DNA is compared.

Historically, much canine genetic research has relied upon reference genomes originating from other breeds. The presentation specifically contrasted the commonly used German Shepherd reference with the new Standard Poodle assembly.

Why does that matter?

Because another breed’s genome may not contain or adequately represent DNA sequences that are specific to Standard Poodles.

Dr. Friedenberg described this as potentially creating a blind spot for Poodle genetics.

The researchers have now built a Standard Poodle reference genome, using DNA collected from a healthy male Standard Poodle who was 11 years old at the time of collection.

The new assembly captures Poodle-specific sequence and resolves both copies of each chromosome.

In everyday terms:

Researchers now have a much better Poodle-specific map to work from.

They haven’t found “the Addison’s gene.” But they have built a better tool for finding genetic differences that earlier approaches may have missed.

Researchers Are Looking at Structural Variants

This leads to another area of ongoing research: structural variation.

When most of us think about a genetic mutation, we tend to picture one small error in DNA.

But genetic differences can be much larger.

A section of DNA can be:

• deleted;
• duplicated;
• inserted somewhere it wasn’t before;
• reversed, which is called an inversion; or
• moved to another genomic location, which can involve a translocation.

Collectively, these kinds of larger changes are called structural variants.

Some structural variants are difficult to evaluate with conventional GWAS methods.

The researchers are now investigating structural variants in Standard Poodles and Portuguese Water Dogs. The new Standard Poodle reference genome gives them a much better tool for doing that.

Why Would Addison’s Researchers Want Poodle Crosses?

This was another fascinating part of the presentation.

The researchers are also interested in cross-breed GWAS.

At first, studying Poodle crosses might sound like an odd way to investigate a disease in purebred Standard Poodles. Genetically, however, it makes a great deal of sense.

An F1 cross gets approximately half of its genome from its Poodle parent and half from the other breed.

Suppose an important Addison’s susceptibility region is extremely common in purebred Standard Poodles. Comparing affected Poodles with unaffected Poodles may not reveal it because both groups have it.

In an F1 Poodle cross, however, researchers can distinguish areas of Poodle ancestry from areas inherited from the other breed.

They can then essentially ask:  When a Poodle cross develops Addison’s, is there a particular piece of Poodle DNA that keeps showing up?

If affected crosses consistently inherit a particular Poodle-derived genomic region while unaffected crosses do not, that could help researchers locate a susceptibility region that has been very difficult to see within the purebred population.

And Then There Was the Spay/Neuter Finding

This will probably be the part of the presentation that generates the most discussion.

Researchers conducted a large environmental risk-factor survey involving Standard Poodles and Portuguese Water Dogs in the United States and Canada.

The survey included 358 Addison’s cases and 4,689 controls and asked approximately 50 questions covering a broad range of possible environmental exposures. The researchers also incorporated environmental data involving factors such as soil, air quality, and water quality.

The resulting study was published in the Journal of Veterinary Internal Medicine in 2023. (PubMed Central (PMC))

One association stood out: spay/neuter status.

After statistical adjustment, the results presented were:

The association was statistically significant in both sexes and considerably stronger in males.

An odds ratio tells us how the odds of an outcome differ between groups. An odds ratio greater than 1 indicates increased odds in the group being studied.

But this finding needs to be interpreted very carefully.

Association does not prove causation.

The researchers are not saying that spaying or neutering causes Addison’s disease.

This was an observational study, not an experiment in which otherwise identical dogs were randomly assigned to remain intact or be altered.

The researchers also looked at timing, and most of the affected dogs had been altered before their Addison’s diagnosis. That makes the relationship worth investigating further, but it still does not prove that gonadectomy caused the disease.

The presentation summarized the finding appropriately: the research suggests a possible role for spay/neuter in the onset of Addison’s, the association appears stronger in males than females, other studies have reported supporting evidence, the mechanism remains unclear, and this finding does not mean “don’t spay/neuter your dog.”

So this is not a reason to panic or make sweeping recommendations.

It is a reason to keep watching the research.

What Does All of This Mean for Breeders?

For me, this was the most important overall message of the presentation.

The emerging picture of Addison’s in Standard Poodles is not:  one bad gene → Addison’s disease.

It appears much more likely that we are dealing with some combination of:  genetic susceptibility + multiple genetic modifiers + immune-system factors + possible structural variants + environmental and/or hormonal influences + factors we haven’t identified yet.

We do not yet know how all of those pieces fit together, and we should not treat that conceptual model as though researchers have proven the complete disease pathway.

But it does help explain something breeders have observed for generations: Addison’s does not behave like the simple recessive diseases for which we can identify carriers and plan breedings around a single mutation.

That also has implications for how we respond when Addison’s appears in a pedigree.

An affected dog is important information. An affected sibling, parent, offspring or other close relative is important information. We absolutely should be tracking it.

But if some of the underlying susceptibility is already widespread within Standard Poodles, attempting to eliminate every dog related to an Addisonian dog could shrink our gene pool substantially without actually eliminating the underlying susceptibility.

For breeders, this remains a matter of risk management rather than genetic purging.

Knowing what occurs in our pedigrees matters. Maintaining contact with puppy owners matters. Tracking health across an entire lifetime matters. Sharing accurate information matters.

And genetic diversity matters, too.

What Can Poodle Breeders and Owners Do to Help?

This is where we can actually contribute.

The research is ongoing. The University of Minnesota lists the current project, Understanding the Drivers of Addison’s Disease in Standard Poodle Dogs, as active through 2028 and funded by the Poodle Club of America Foundation. (Experts@Minnesota)

The researchers need dogs and good information.

If you own or know of a Standard Poodle recently diagnosed with Addison’s disease, please contact the University of Minnesota research team.

Email: [email protected]

The University of Minnesota’s current study information says affected Standard Poodles of any age may qualify, with diagnosis documented by an ACTH stimulation test and other clinical information. The study is also interested in unaffected Standard Poodles at least eight years old with no history of Addison’s or another autoimmune disease as controls. International submissions of affected dogs are welcome, while sample-shipping requirements affect enrollment of controls outside the United States and Canada. (College of Veterinary Medicine) He stated they already have enough data from healthy younger standard poodles.

University of Minnesota Addison’s Disease Genetics Study in Standard Poodles

And don’t underestimate the value of health information from the dogs we have bred.

Keep lifetime records. Stay in touch with puppy owners. Record confirmed diagnoses. Keep track of age at diagnosis. Record spay/neuter status and, when possible, the age at which the dog was altered. Maintain pedigrees and family health histories.

An older healthy Poodle can be scientifically valuable, too. Researchers need controls, meaning dogs without the disease against which affected dogs can be compared. In fact, an older unaffected dog is particularly useful because researchers can be more confident that the dog has remained unaffected over a substantial portion of its lifetime.

Credit Where Credit Is Due

The information summarized here comes from the presentation by Dr. Steven Friedenberg and the research he and his collaborators have conducted on Addison’s disease.

The presentation acknowledged collaborators at the University of Minnesota and University of Georgia, as well as Carole Grundy in the UK, and most importantly the breeders, owners and dogs who have contributed samples.

The work presented has received funding and support from the Poodle Club of America Foundation, American Kennel Club Canine Health Foundation, Portuguese Water Dog Foundation/PWD Club of the Twin Cities, and National Institutes of Health. The University of Minnesota confirms that the Poodle Club of America Foundation continues to fund Dr. Friedenberg’s current Standard Poodle Addison’s research. (Experts@Minnesota)

My Biggest Takeaway

We haven’t solved Addison’s disease in Standard Poodles.

But I came away from this presentation feeling that researchers have a much clearer understanding of why it has been so difficult to solve and much better tools for asking the next questions.

They are looking beyond conventional GWAS. They are examining immune-system genetics. They are investigating structural variation. They now have a Standard Poodle-specific reference genome. They are looking at environmental and hormonal associations. And they are exploring cross-breed studies as a way of finding Poodle genetic susceptibility that may be extremely difficult to detect by comparing one Standard Poodle with another.

For those of us who breed and love Standard Poodles, perhaps the most useful thing we can contribute right now is good data.

Accurate diagnoses.

Accurate pedigrees.

Lifetime health information.

Samples from affected dogs and appropriate healthy controls.

And a willingness to share that information with the researchers who can actually use it.

Every well-documented dog, affected or unaffected, adds another piece to a puzzle that researchers have been working for years to solve.