title: Genetic control of canine leishmaniasis: genome-wide association study and genomic selection analysis.
abstract: BACKGROUND
  The 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.
  
  
  RESULTS
  Genome-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
  We 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).
authors.affiliation: Departament de Genètica Animal, Centre de Recerca en Agrigenòmica, CRAG, Universitat Autònoma de Barcelona, Barcelona, Spain. javier.quilez@cragenomica.es
authors.forename: Javier
authors.initials: J
authors.lastname: Quilez
authors.forename: Verónica
authors.initials: V
authors.lastname: Martínez
authors.forename: John A
authors.initials: JA
authors.lastname: Woolliams
authors.forename: Armand
authors.initials: A
authors.lastname: Sanchez
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pong-Wong
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Kennedy
authors.forename: Rupert J
authors.initials: RJ
authors.lastname: Quinnell
authors.forename: William E R
authors.initials: WE
authors.lastname: Ollier
authors.forename: Xavier
authors.initials: X
authors.lastname: Roura
authors.forename: Lluís
authors.initials: L
authors.lastname: Ferrer
authors.forename: Laura
authors.initials: L
authors.lastname: Altet
authors.forename: Olga
authors.initials: O
authors.lastname: Francino
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D002874:Chromosome Mapping; D018450:Disease Progression; D004283:Dog Diseases / Q000235:genetics* / Q000503:physiopathology*; D004285:Dogs; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D007896:Leishmaniasis / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D016013:Likelihood Functions; D051379:Mice; D015233:Models, Statistical; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012372:ROC Curve; D012680:Sensitivity and Specificity
chemical_list: D005819:Genetic Markers