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Cited by 179Human-Animal Interaction StudiesGenetic and phenotypic traits in livestockGenetic Mapping and Diversity in Plants and Animals

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Genetic mapping of canine fear and aggression

Open access
Zapata, Isain, Serpell, James A., Alvarez, Carlos E.·2016·BMC Genomics
DOI 10.1186/s12864-016-2936-3PMC PMC4977763
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Abstract

BACKGROUND: Fear/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. RESULTS: We 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. CONCLUSIONS: We 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.

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Fig. 1 PCA analysis of behavioral traits. Since the two GWA datasets only partially overlapped in breed content, PCA analysis was performed to evaluate if the breed makeup affects the distribution structure of the variables. a, b Component pattern and component scores, respectively, of C-BARQ behavioral traits on the matching breeds in the Boyko dataset. c, d Component pattern and component scores of C-BARQ behavioral traits on the matching breeds in the Vaysse dataset
Fig. 1 PCA analysis of behavioral traits. Since the two GWA datasets only partially overlapped in breed content, PCA analysis was performed to evaluate if the breed makeup affects the distribution structure of the variables. a, b Component pattern and component scores, respectively, of C-BARQ behavioral traits on the matching breeds in the Boyko dataset. c, d Component pattern and component scores of C-BARQ behavioral traits on the matching breeds in the Vaysse datasetCC BY · PubMed Central
Fig. 2 Manhattan plots of C-BARQ aggression traits. Vertical lines indicate relevant and consistent hits across the two GWA datasets. In each panel, the top plot corresponds to the Vaysse dataset while the bottom plot corresponds to Boyko dataset. a Stranger-directed aggression. b Dog-directed aggression. c Owner-directed aggression. d Dog rivalry
Fig. 2 Manhattan plots of C-BARQ aggression traits. Vertical lines indicate relevant and consistent hits across the two GWA datasets. In each panel, the top plot corresponds to the Vaysse dataset while the bottom plot corresponds to Boyko dataset. a Stranger-directed aggression. b Dog-directed aggression. c Owner-directed aggression. d Dog rivalryCC BY · PubMed Central
Fig. 3 Manhattan plots of C-BARQ fear traits. Vertical lines indicate relevant and consistent hits across the two GWA datasets. In each panel, the top plot corresponds to Vaysse dataset while the bottom plot corresponds to Boyko dataset. a Stranger-oriented fear. b Dog-oriented fear. c Nonsocial-oriented fear. d Separation-related anxiety. e Touch-sensitivity
Fig. 3 Manhattan plots of C-BARQ fear traits. Vertical lines indicate relevant and consistent hits across the two GWA datasets. In each panel, the top plot corresponds to Vaysse dataset while the bottom plot corresponds to Boyko dataset. a Stranger-oriented fear. b Dog-oriented fear. c Nonsocial-oriented fear. d Separation-related anxiety. e Touch-sensitivityCC BY · PubMed Central
Fig. 4 Success/failure matrix of predicted values. Green fill indicates a successful prediction and red is a failed prediction. Columns correspond to aggression and fear traits while rows correspond to dog breeds predicted. Totals are the sum of successful prediction within the column/row; columns and rows are sorted in numerical order and cells have a fill color gradient that goes from red (worse) to green (best)
Fig. 4 Success/failure matrix of predicted values. Green fill indicates a successful prediction and red is a failed prediction. Columns correspond to aggression and fear traits while rows correspond to dog breeds predicted. Totals are the sum of successful prediction within the column/row; columns and rows are sorted in numerical order and cells have a fill color gradient that goes from red (worse) to green (best)CC BY · PubMed Central
Fig. 5 Haplotype distribution across dog breeds based on novel chr18 and X markers associated with aggression and fear. Haplotypes were defined only on the alleles of the top markers detected in this study. Allele distributions are color coded on a gradient that goes from yellow (fixed for allele 1) to blue (fixed for allele 2). Allele label letters are arbitrary
Fig. 5 Haplotype distribution across dog breeds based on novel chr18 and X markers associated with aggression and fear. Haplotypes were defined only on the alleles of the top markers detected in this study. Allele distributions are color coded on a gradient that goes from yellow (fixed for allele 1) to blue (fixed for allele 2). Allele label letters are arbitraryCC BY · PubMed Central
Fig. 6 Linkage Disequilibrium plots for chr18/X fear and aggression loci. a Chr18 GWA locus for fear/aggression (using C-BARQ phenotypes and the Vaysse genotype dataset). b ChrX locus for the same GWAS as a. Genomic coordinates are converted from CanFam2 to CanFam3, and gene information is from the Broad Institute’s CanFam3 Improved Annotation Data v.1. * OLFR1323 is a mouse name gene; in dog, the name is ENSCAFG00000018811 (Protein Coding Gene). Linkage disequilibrium plot was created with Haploview v.4.2
Fig. 6 Linkage Disequilibrium plots for chr18/X fear and aggression loci. a Chr18 GWA locus for fear/aggression (using C-BARQ phenotypes and the Vaysse genotype dataset). b ChrX locus for the same GWAS as a. Genomic coordinates are converted from CanFam2 to CanFam3, and gene information is from the Broad Institute’s CanFam3 Improved Annotation Data v.1. * OLFR1323 is a mouse name gene; in dog, the name is ENSCAFG00000018811 (Protein Coding Gene). Linkage disequilibrium plot was created with Haploview v.4.2CC BY · PubMed Central
Fig. 7 Mapping phased-haplotypes and S i/D i regions for fear/aggression traits. Quantitative trait with increased-fear/aggression associated with the C allele. Letters on the left indicate the fixed allele required for phasing. Red line is the peak SNP for fear/aggression GWA. The large window size corresponds to 1.50 Mb, and small to 812.1 kb. Green-white gradient shading represents larger-smaller fear/aggression risk. Diagonal lines indicate missing phenotype data
Fig. 7 Mapping phased-haplotypes and S i/D i regions for fear/aggression traits. Quantitative trait with increased-fear/aggression associated with the C allele. Letters on the left indicate the fixed allele required for phasing. Red line is the peak SNP for fear/aggression GWA. The large window size corresponds to 1.50 Mb, and small to 812.1 kb. Green-white gradient shading represents larger-smaller fear/aggression risk. Diagonal lines indicate missing phenotype dataCC BY · PubMed Central
Fig. 8 Mapping phased-haplotypes and S i /D i regions for fear/aggression traits. Quantitative trait with decreased-fear/aggression associated with the G allele. Letters on the left indicate the fixed allele required for phasing. Red line is the peak SNP for fear/aggression GWA, orange is for sociability peak and purple is for size peak. The large window size corresponds to 5.20 Mb, and small to 2.00 Mb. Green-white gradient shading represents larger-smaller fear/aggression risk. Diagonal lines indicate missing phenotype data. * OLFR1323 is a mouse name gene; in dog, the name is ENSCAFG00000018811 (Protein Coding Gene)
Fig. 8 Mapping phased-haplotypes and S i /D i regions for fear/aggression traits. Quantitative trait with decreased-fear/aggression associated with the G allele. Letters on the left indicate the fixed allele required for phasing. Red line is the peak SNP for fear/aggression GWA, orange is for sociability peak and purple is for size peak. The large window size corresponds to 5.20 Mb, and small to 2.00 Mb. Green-white gradient shading represents larger-smaller fear/aggression risk. Diagonal lines indicate missing phenotype data. * OLFR1323 is a mouse name gene; in dog, the name is ENSCAFG00000018811 (Protein Coding Gene)CC BY · PubMed Central

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Metadata

Authors
Zapata, I., Serpell, J. A., & Alvarez, C. E.
Affiliations
  • Nationwide Children's Hospital (US)
  • University of Pennsylvania (US)
Corresponding author
Alvarez, Carlos E.
ORCID
Venue
BMC Genomics
Publisher
Springer Science and Business Media LLC
Published
2016-08-08
Volume
17
Issue
1
Pages
572-572
ISSN
1471-2164 (ISSN-L)
DOI
10.1186/s12864-016-2936-3
PMC
PMC4977763
OpenAlex
W2518047727
Cited by
168
References
80
Citations by year
2026: 14 · 2025: 17 · 2024: 19 · 2023: 26 · 2022: 20 · 2021: 14 · 2020: 16 · 2019: 18 · 2018: 11 · 2017: 10 · 2016: 3
FWCI
11.30
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Genomics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Congressionally Directed Medical Research Programs (W81XWH-11-2-0224)
  • American Kennel Club Canine Health Foundation (01660)
  • Morris Animal Foundation (D13CA-073)
Topics
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Human-Animal Interaction Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
insulin-like growth factor I, HMGA2, IGSF1, separation anxiety, tactile sensitivity, sociability, amygdala, hypothalamic-pituitary-adrenal axis
MeSH terms
Aggression, Alleles, Animals, Behavior, Animal, Breeding, Chromosome Mapping, Dogs, Fear, Haplotypes, Linkage Disequilibrium, Genome, Genome-Wide Association Study, Genetic Association Studies

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