Genetic mapping of canine fear and aggression

Abstract

BackgroundFear/anxiety and anger/aggression greatly influence health, quality of life and social interactions. They are a huge burden to wellbeing, and personal and public economics. However, while much is known about the physiology and neuroanatomy of such emotions, little is known about their genetics – most importantly, why some individuals are more susceptible to pathology under stress.ResultsWe conducted genomewide association (GWA) mapping of breed stereotypes for many fear and aggression traits across several hundred dogs from diverse breeds. We confirmed those findings using GWA in a second cohort of partially overlapping breeds. Lastly, we used the validated loci to create a model that effectively predicted fear and aggression stereotypes in a third group of dog breeds that were not involved in the mapping studies. We found that i) known IGF1 and HMGA2 loci variants for small body size are associated with separation anxiety, touch-sensitivity, owner directed aggression and dog rivalry; and ii) two loci, between GNAT3 and CD36 on chr18, and near IGSF1 on chrX, are associated with several traits, including touch-sensitivity, non-social fear, and fear and aggression that are directed toward unfamiliar dogs and humans. All four genome loci are among the most highly evolutionarily-selected in dogs, and each of those was previously shown to be associated with morphological traits. We propose that the IGF1 and HMGA2 loci are candidates for identical variation being associated with both behavior and morphology. In contrast, we show that the GNAT3-CD36 locus has distinct variants for behavior and morphology. The chrX region is a special case due to its extensive linkage disequilibrium (LD). Our evidence strongly suggests that sociability (which we propose is associated with HS6ST2) and fear/aggression are two distinct GWA loci within this LD block on chrX, but there is almost perfect LD between the peaks for fear/aggression and animal size.ConclusionsWe have mapped many canine fear and aggression traits to single haplotypes at the GNAT3-CD36 and IGSF1 loci. CD36 is widely expressed, but areas of the amygdala and hypothalamus are among the brain regions with highest enrichment; and CD36-knockout mice are known to have significantly increased anxiety and aggression. Both of the other genes have very high tissue-specificity and are very abundantly expressed in brain regions that comprise the core anatomy of fear and aggression – the amygdala to hypothalamic-pituitary-adrenal (HPA) axis. We propose that reduced-fear variants at these loci may have been involved in the domestication process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2936-3) contains supplementary material, which is available to authorized users.

The influence of X chromosome variants on trait neuroticism

“…Two isoforms identified by cDNA cloning in humans showed the long form to be expressed in brain-related tissue 39 . Sociability traits (attitude to human strangers) have been previously mapped to HS6ST2 in dogs 35 , with the neurobiological pathways involved in these emotions highly conserved in vertebrates 40,41 . We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans, particularly in the transmembrane and NTP hydrolase domains.…”

“…Because HS6ST2 was the only gene within which single SNPs attained significance, was mapped within the key region at Xp26.2, and had been implicated in a relevant behavioural trait in the dog 35 , it was investigated further. A phylogenetic tree was constructed from all available orthologous sequences (Supplementary Figure 12) and showed that the dog sequence was in a group with the cat and leopard, and close to the horse, another companion animal, and to the alpaca, a domesticated species.…”

Highly Heritable and Functionally Relevant Breed Differences in Dog Behavior

“…However, research to date has been conducted with small sample sizes from a restricted number of breeds, limiting our ability to make inferences about the evolution and biological basis of behavioral diversity across breeds (15,16).…”

Candidate SNP markers of aggressiveness-related complications and comorbidities of genetic diseases are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters

“…The complexity of the problem stems from multifactorial neuroendocrine physiological regulatory mechanisms that are based on genetic systems such as epigenetic regulation of aggressive behavior. For this reason, genome-wide studies of this vitally important form of human behavior are only at the rudimentary stage (e.g., [10]).…”