Widespread genetic testing controls inherited polycystic kidney disease while avoiding inbreeding in cats

Abstract Background Polycystic kidney disease (PKD) is a major hereditary disorder characterized by the formation of cysts in the kidneys of mammals, including humans and cats. It commonly leads to renal failure and is frequently associated with variants in the PKD1 gene. In cats, a specific PKD1 variant (chr E3:g.42858112 C > A) is a primary target for direct-to-consumer (DTC) genetic testing aimed at identifying PKD risk. However, its broad impact on the genetic structure of cat populations remains unclear. In this study, we investigated temporal and breed-specific dynamics of feline PKD and the PKD1 variant using a large-scale dataset comprising 110,325 insured cats and 61,968 genetically tested cats across 14 breeds in Japan. Results Our comprehensive analysis of insured cats revealed no clear differences in claim-based detection of cystic kidneys across breeds, sexes, or ages, although notable geographic variations were observed. Among the cats diagnosed with cystic kidneys, 77.8% carried the conventional PKD1 variant. Exome and whole-genome sequencing of affected cats revealed eight potentially deleterious variants in PKD-related genes, suggesting the involvement of other genetic factors. The carrier frequency of the PKD1 variant in all 14 breeds decreased by 42.6% when comparing genetic data from 2019, when full-scale genetic testing for kittens began, and 2022. In additional analyses focusing on eight breeds with larger sample sizes, significant reductions in the proportion of heterozygous cats were observed in Scottish Folds, Persians, and Ragamuffins (49.5%, 38.8%, and 57.7% decrease, respectively) between the two time points. In contrast, no statistically significant or suggestive reductions were observed in British Shorthairs, Minuets, or Munchkins. Further genomic analyses in Scottish Folds and Persians indicated no substantial changes in overall genetic structure or inbreeding levels; however, the effective population size of cats harboring the PKD1 variant declined between these periods. Conclusions These findings highlight the role of DTC genetic testing in promoting optimized breeding strategies that contribute to reducing PKD risk while avoiding inbreeding and enhancing feline welfare. To further reduce the number of risk variants, promoting genetic testing and ensuring appropriate breeding practices is necessary, particularly for breeds in which a decrease in PKD1 variants has not been observed.