Dogs Guide Search for Genes in Panic and Anxiety

By Jeffrey Norris Most dogs bring joy to families, but UCSF geneticist and psychiatrist Steven Hamilton, MD, PhD, does not focus on the joy-inducing aspects of dogs. Instead, he wants to identify and understand the genetic background of panic and anxiety-related disorders, obsessive-compulsive disorders, and aggression. Many individual dogs exhibit these behavioral syndromes. Owners may be unable to manage, modify or tolerate these undesirable behaviors. Many dogs end up abandoned, in pounds or euthanized as a result. In fact, Melanie Chang, PhD, a postdoctoral fellow with Hamilton's lab group, became interested in Hamilton's research through her own experiences with her rescued border collie, Solo, a still-beloved pet that initially required Chang's constant attention. Hamilton is not in any way an advocate for breed bans. Nor does the goal of his genetics research have anything to do with canine eugenics. It's actually breeders who recently have taken an interest in using modern science to control disease-related doggie DNA. It is possible that Hamilton's research will eventually lead to innovative ways of treating or training troubled tail-waggers. But Hamilton would not be doing the research if he did not also believe that troubled dogs can provide insight into troubled humans. "We know that dogs have syndromes that are very similar to human disorders," he says. Breeders' Experiments Unraveling the contribution of genetics to behavior has long been a challenge. But dog populations are much less genetically complex than human populations. Sorting through data from genetic studies of dogs is expected to be less confounding. "The genetic architecture of the species facilitates finding genes in individual breeds," Hamilton says.

Border collies Fly and Solo at San Francisco's Crissy Field. Melanie Chang, a postdoctoral fellow, became interested in UCSF researcher Steve Hamilton's search for genes associated with phobias through her own experiences with Solo, a rescued dog. Solo initially required Chang's constant attention.

That's because, in a way, dogs have always been subject to breeding experiments. Comparisons of DNA across species and breeds suggest that our ancestors began domesticating dogs from wolves as long as 100,000 years ago. In earlier centuries, dogs were bred for different behavioral traits useful for work, such as herding, hauling, guarding and hunting. Like humans, dogs are a single species, Canis familiaris. But since the 1800s, kennel clubs in the United States - especially the American Kennel Club (AKC) - have helped catalyze a proliferation of distinct breeds. And the AKC keeps extensive records of registered pedigrees. Each registered dog must be purebred according to standards that help ensure that each dog within a breed conforms to well-defined physical characteristics. As a result, dogs within breeds are genetically very similar. Sometimes undesirable traits, due to what Hamilton calls "hitchhiking genes," are passed on with genes that confer sought-after, breed-defining characteristics. Hundreds of genetic diseases have become common in some of the more than 150 or so breeds recognized by the AKC. But while individual breeds are inbred, different breeds can be genetically quite different from one another. "The differences between any two breeds can be greater than the differences we see between any two human populations," Hamilton says. This similarity within breeds and variability across breeds make it easier for researchers to search for disease genes in dogs. Within breeds, distinctive variations in inherited DNA that may be linked to a disease will be more conspicuous against a background of relatively little genetic variation. The disease is likely to be caused by the same inherited DNA in all the dogs within a breed that exhibit the disorder. Similarly, because identical genetic variations are less likely to be found across different breeds, it may be easier to pick out any such variations that are present and that are associated with genetic diseases that similarly afflict individual dogs across different species. Hamilton's co-leader for the Canine Behavioral Genetics Project is Karen Overall, VMD, PhD, a research associate at the University of Pennsylvania and an expert on veterinary behavioral medicine. Hamilton and Overall believe that dogs may serve as a model from which researchers may learn more about many human behavioral disorders. Dog DNA Goes Mainstream The pace of genetic studies of diseases in dogs has quickened recently. In 2005, federally funded researchers completed a detailed map of dog genes - the dog genome - with DNA courtesy of a female boxer. Commercial companies now offer up-to-date lab tests, "chips" for comparing dog DNA, just as they do for human DNA. Even before gene maps and high-tech gene-tracking tests became available, researchers had already recognized the value of studying human diseases in dogs. For example, a gene mutation that causes narcolepsy - in which individuals are inclined to suddenly fall asleep at inopportune times - was first identified in dogs in 1999. A deficit of the protein encoded by the same gene was found to be the cause of human narcolepsy a year later. With better tools, researchers now are studying dogs to identify genetic contributions to complex illnesses such as cancer and heart disease. After the Canine Behavioral Genetics Project began in 2004 with support from the McKnight Endowment Fund for Neuroscience, Hamilton's lab team began sending out kits to interested dog owners, receiving back in the mail cheek swabs covered with dog DNA, as well as owners' survey responses. Thousands of DNA samples now are stored in lab freezers. They come from purebreds and mutts, normal dogs and dogs with behavioral disorders. With help from pet owners, the researchers are putting together pedigrees as best they can for dogs in the study. Breeders, wary of calling attention to undesirable, inherited traits, have not been a major source of information.

Geneticists who study diseases in families track inheritance of genes across generations. They look for the presence of genes in individuals with and without the disease of interest. Researchers construct pedigrees such as this one, similar to a family tree in its representation of different generations. Circles represent females and boxes represent males. Black-filled shapes identify individuals affected by disease. (See larger)

Phobias in Pets and People Thanks largely to Chang's involvement in the community of border collie enthusiasts, the project has an especially good representation of that breed. Border collies were originally selected for breeding based on livestock-herding ability. As with other breeds, some border collies exhibit noise phobia. It's an easy-to-identify behavior, and it is "common enough," Hamilton says, to fruitfully study. A dog with noise phobia exhibits a fear response triggered by thunderstorms or local fireworks celebrations. The dog's heart races. It may shake or freeze, or defecate or urinate uncontrollably. If it's home alone, it may try to escape, chewing on doors or even jumping from windows. A dog without noise phobia does not "panic" in this way when subjected to the same noises. Humans with specific phobias - fear of spiders or heights, for instance - and those with panic disorders also exhibit distinct physiological symptoms during their intensely anxious episodes. Hamilton also is studying humans with anxiety disorders, including panic disorder. He expects the dog studies to give the human studies a boost. Just as dog breeders keep track of pedigrees, human geneticists construct pedigrees to trace diseases within susceptible families. "We have the world's largest collection of human panic disorder pedigrees - 120 of them - with about 1,000 DNA samples," Hamilton says. "We have been trying to map genes for panic disorder, but we are struggling because the linkages we are finding between DNA sequences and the disorder are not very strong. That's one of the motivations we have for looking at the dog. "If we find a gene or set of genes that are associated with panic-like disorders in the dog, we can go back and look more closely in our samples from human families at the human forms of those genes." Finding genetic variants associated with panic disorders should lead to a better understanding of the biochemistry that helps trigger them and, it is hoped, to better targeted treatments. Photo/Melanie Chang Related Links: UCSF Researcher Tracks Genes that Predict Response to Antidepressants UCSF Today, June 15, 2007 UCSF Canine Behavioral Genetics Project The NHGRI Dog Genome Project National Human Genome Research Institute, National Institutes of Health Dog Star Rising: The Canine Genetic System (PDF file) Nature, December 2004 Prozac for Your Dog Technology Review, March 30, 2007 As Breeders Test DNA, Dogs Become Guinea Pigs New York Times, June 12, 2007 Medicine: Initiative Aims to Merge Animal and Human Health Science to Benefit Both Science, June 15, 2007 The McKnight Foundation