Bayesian mixed model analysis uncovered 21 risk loci for chronic kidney disease in boxer dogs

by Frode Lingaas, Katarina Tengvall, Johan Høgset Jansen, Lena Pelander, Maria H. Hurst, Theo Meuwissen, Åsa Karlsson, Jennifer R. S. Meadows, Elisabeth Sundström, Stein Istre Thoresen, Ellen Frøysadal Arnet, Ole Albert Guttersrud, Marcin Kierczak, Marjo K. Hytönen, Hannes Lohi, Åke Hedhammar, Kerstin Lindblad-Toh, Chao Wang

Chronic kidney disease (CKD) affects 10% of the human population, with only a small fraction genetically defined. CKD is also common in dogs and has been diagnosed in nearly all breeds, but its genetic basis remains unclear. Here, we performed a Bayesian mixed model genome-wide association analysis for canine CKD in a boxer population of 117 canine cases and 137 controls, and identified 21 genetic regions associated with the disease. At the top markers from each CKD region, the cases carried an average of 20.2 risk alleles, significantly higher than controls (15.6 risk alleles). An ANOVA test showed that the 21 CKD regions together explained 57% of CKD phenotypic variation in the population. Based on whole genome sequencing data of 20 boxers, we identified 5,206 variants in LD with the top 50 BayesR markers. Following comparative analysis with human regulatory data, 17 putative regulatory variants were identified and tested with electrophoretic mobility shift assays. In total four variants, three intronic variants from the MAGI2 and GALNT18 genes, and one variant in an intergenic region on chr28, showed alternative binding ability for the risk and protective alleles in kidney cell lines. Many genes from the 21 CKD regions, RELN, MAGI2, FGFR2 and others, have been implicated in human kidney development or disease. The results from this study provide new information that may enlighten the etiology of CKD in both dogs and humans.