Genome scans of dog behavior implicate a gene network underlying psychopathology in mammals, including humans

Abstract

Genetic studies show a general factor associated with all human personality and psychopathology, 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 five 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, 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 dog behavior is correlated with body size, we isolated the effect of body size/height in the dog mapping and in the comparative human UK Biobank analyses. Our dog and human findings are consistent with pleiotropy of diverse brain traits with energy metabolism, height, longevity and reproduction. We propose a genetic network underlies neuron birth and development across the life course, and is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for all common psychiatric disorders, and suggests how their risk could be impacted by environmental effects on the IGF1/growth factor signaling-PI3K-AKT-mTOR axis.

Genetic testing of dogs predicts problem behaviors in clinical and nonclinical samples

“…One consistently-detected association was between genetic markers and small body size (using weight as a proxy). We previously reported this and the association of small size and problem behaviors 11,12 , which are supported by behavioral [17][18][19][20] and other genetic evidence 22 . Pedigree breed and Pit Bull-type represent reduced variation, and, thus predictably, showed association with subsets of markers.…”

“…We observed correlations between markers on different chromosomes, such as 10, 18, 24, 32 and X. This is presumably due to genetic stratification across breeds, but it should be noted that the present loci are likely to be enriched for admixture 26 and possibly selection in early domestication 11,12 (may not reflect vertical breed-relatedness). Supporting this, correlated markers were not correlated with the same traits.…”

“…Strong positive selection in dog domestication and breed development had the by-effect of vastly relaxed negative selection. As a result, most complex traits studied to date in dogs -including cancer and other diseases, morphology and behavior -have shown dramatically-reduced polygenicity and moderate-to-large effect sizes of associated variants 3,[5][6][7][8][9][10][11][12][13] . In contrast, common human complex disease variations generally have small effect sizes and are not directly useful medically or experimentally.…”

“…We previously reported genome wide association studies (GWASs) of breed averages for fear and aggression behaviors in multiple cohorts with different breed make-ups 11,12 . That was based on behavioral data using the validated survey instrument C-BARQ [14][15][16] .…”

“…In a study partnered with the present work, we compared the scans of diverse behaviors with and without correction for body mass. The correlation of body size and behavior in dogs has thus been observed in behavioral [17][18][19][20] and genetic studies 11,12 . Based on biological relevance, we previously argued that behavior-body size correlations are due to pleiotropy 12 (rather than population structure 21 ).…”