Genome scans of diverse dog behaviors implicate a neurodevelopmental gene network in mammalian adaptation and psychopathology

Abstract

Genetic studies show a general factor associated with all human psychopathology and strongly correlated with personality and intelligence, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi-breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort. Several of those loci were also associated with brain structure differences across breeds; and six of the respective top-candidate genes are also associated with human brain structure and function. More broadly, the geneset of canine behavioral scans is supported by enrichment for genes mapped for human behavior, personality, cognition, psychopathology and brain structure. The biology implicated includes, neurogenesis, axon guidance, angiogenesis, brain structure, alternative splicing, disease association, Hox-family transcription factors, and subiculum expression. Because body size and behavior are correlated in dogs, we isolated the effect of body size in the dog mapping and in the comparative human UK Biobank analyses. Our dog findings are consistent with pleiotropy of diverse brain traits with energy metabolism and growth, and suggest behavioral variations often affect neurogenesis. There is support for such pleiotropy in humans and well-powered genetic studies of human psychiatric traits consistently implicate neurogenesis. We propose a genetic network which underlies neuron birth and development throughout life is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for genetic and environmental contributions to psychiatric disease. We discuss how canine translational models can further accelerate the study of psychopathology. Author summaryWe genetically mapped diverse normal and problem behaviors in dogs. The well-established approach we used is ideally suited for finding variation that is common across dog breeds and for pin-pointing the most likely gene candidates. Our analysis of the genes implicated at 90 genome regions shows they are enriched for i) genes mapped for diverse brain functions and pathologies in humans; ii) genes involved in brain development throughout life; and iii) footprints of evolution in dogs, humans and other animals. We propose that is consistent with evolutionary conservation of the general genetic factor of mental health in humans, which is correlated with personality and intelligence. The implications are that this super-network of genes is preferentially targeted by evolutionary adaptation for behavior and that its dysregulation increases risk of mental health disorders.