Abstract
BackgroundThe current disease model for leishmaniasis suggests that only a proportion of infected individuals develop clinical disease, while others are asymptomatically infected due to immune control of infection. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, although previous studies suggest a role for host genetics. Our hypothesis was that canine leishmaniasis is a complex disease with multiple loci responsible for the progression of the disease from Leishmania infection.Methodology/Principal FindingsGenome-wide association and genomic selection approaches were applied to a population-based case-control dataset of 219 dogs from a single breed (Boxer) genotyped for ∼170,000 SNPs. Firstly, we aimed to identify individual disease loci; secondly, we quantified the genetic component of the observed phenotypic variance; and thirdly, we tested whether genome-wide SNP data could accurately predict the disease.Conclusions/SignificanceWe estimated that a substantial proportion of the genome is affecting the trait and that its heritability could be as high as 60%. Using the genome-wide association approach, the strongest associations were on chromosomes 1, 4 and 20, although none of these were statistically significant at a genome-wide level and after correcting for genetic stratification and lifestyle. Amongst these associations, chromosome 4: 61.2–76.9 Mb maps to a locus that has previously been associated with host susceptibility to human and murine leishmaniasis, and genomic selection estimated markers in this region to have the greatest effect on the phenotype. We therefore propose these regions as candidates for replication studies. An important finding of this study was the significant predictive value from using the genomic information. We found that the phenotype could be predicted with an accuracy of ∼0.29 in new samples and that the affection status was correctly predicted in 60% of dogs, significantly higher than expected by chance, and with satisfactory sensitivity-specificity values (AUC = 0.63).
Highlights
Leishmaniasis is a vector-borne disease affecting humans and animals, caused by parasitic species of the genera Leishmania and transmitted by the bite of phlebotomine sand flies
Genetic susceptibility to progression of disease from Leishmania infection is supported by the fact that the percentage of infected dogs in endemic areas is as high as 60% [20] whereas rates of clinical canine leishmaniasis (CanL) are much lower in these areas [21,22]
Healthy infected and affected samples generally clustered together in the Multidimensional scaling (MDS) plot (Figure S2), genetic stratification was observed in our cleaned dataset based on the genomic inflation factor (l = 1.29), with C1 capturing twice the stratification captured by C2
Summary
Leishmaniasis is a vector-borne disease affecting humans and animals, caused by parasitic species of the genera Leishmania and transmitted by the bite of phlebotomine sand flies. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, but previous studies suggest a large contribution of the host genetic background, as reviewed elsewhere [1,2]. To familial aggregation and ethnic differences of leishmaniasis prevalence seen in humans, dog breeds show variable susceptibility to CanL. Some breeds such as Boxer, German shepherd and Rottweiler [23,24,25] appear more predisposed to overt CanL. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, previous studies suggest a role for host genetics. Our hypothesis was that canine leishmaniasis is a complex disease with multiple loci responsible for the progression of the disease from Leishmania infection
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