Abstract
We conducted a Phenome-Wide Association Study (PheWAS) to investigate whether alleles previously shown to be associated with problem behaviors in Labrador Retrievers from the U.S. Transportation Security Administration’s (TSA) odor detection program also show behavioral associations in other populations. The original TSA cohort (2002–2013) consisted of dogs from a former breeding program that drew from U.S. commercial sources and the Australian Customs Service. While those data included TSA testing results from the foster period, detailed behavior profiles and reasons for elimination from the program were not recorded. To extend and validate these genetic associations in populations with richer behavioral data, we analyzed three additional Labrador Retriever cohorts with both genotype and C-BARQ behavioral questionnaire data: (1) Australian pet dogs, (2) UK dogs from a mixed pet and working background (primarily gamebird retrieving), and (3) U.S. working guide dogs. This analysis identified a total of 15 associations between 12 behavioral traits and 8 markers at 6 genome loci. Notably, we found four types of aggression and one type of fear that are directed at familiar humans or dogs, but none directed at unfamiliar ones. Other problem traits identified include separation-related behaviors, excitability, and chasing small animals. Furthermore, we utilized whole genome sequencing to identify a functional candidate associated with “aggression when approached by a household dog at a favorite resting place”. We propose this variant in an ADAMTSL1 intron results in the loss of TCF7L1 protein binding, and we highlight the evolutionary history of that conserved element, including the fixation of two mutations in the human lineage. Our PheWAS findings suggest relevance to working dog selection, breeding, and training, presenting opportunities to reduce costs while improving performance and resilience. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-42708-4.