Abstract
Although genetic factors contribute to behavioral variation in working dogs, the underlying molecular determinants remain poorly understood. The sortilin-related VPS10 domain-containing receptor 1 (SORCS1) gene is highly expressed in the central nervous system and has been implicated in neuronal signaling and synaptic regulation. A preliminary genome-wide association study suggested an association between SORCS1 variants and guide dog training outcomes. However, this result relied on only 28 dogs and lacked sufficient statistical power. In this study, we expanded the sample size and evaluated the association between SORCS1 polymorphisms and behavioral suitability in 160 dogs, using pass/fail training outcomes as behavioral trait indicators. We initially validated 12 candidate SNPs within SORCS1 using Sanger sequencing in 64 dogs, revealing significant genotype-dependent differences for eight loci located in predicted intron 3. A tagging SNP (rs23402730, C > T) was subsequently genotyped in 160 dogs (65 successful and 95 unsuccessful). The strongest association was detected under a recessive model (CC + CT vs. TT), yielding P = 4.7 × 10 ⁻ ⁵ and an odds ratio (OR) of 4.11 (95% CI: 2.07-8.18). As allele frequencies and genetic relatedness varied among dogs, we further evaluated the association using generalized linear mixed-effects models adjusting for sex, breed, and family structure. In the full dataset (n = 159), the additive genotype remained statistically significant (β = 2.20, P = 4.5 × 10 ⁻ 4; OR = 8.98, 95% CI: 2.64-30.59). Moreover, we confirmed the association in a genetically homogeneous subset of 114 Labrador retrievers, independent of breed effects (P = 0.029; OR = 4.71, 95% CI: 1.17-18.99). These results suggest that variation in SORCS1 is associated with behavioral suitability in dogs, based on an expanded cohort with guide dog training outcomes. As behavior is polygenic, SORCS1 represents one contributing locus that may be informative for future genetic studies aimed at elucidating the molecular basis of canine behavior.