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Unravelling the molecular basis of common complex human disorders using the dog as a model system

Periodic Report Summary - LUPA (Unravelling the molecular basis of common complex human disorders using the dog as a model system)

Project context and objectives:

Understanding the pathogenic mechanisms of common human diseases as cancers, cardiovascular or inflammatory disorders, is a major objective of ongoing genomics initiatives. The identification of predisposing genes is promising but difficult due to the complexity of the underlying causes. However human genetic studies can be complemented by genetic studies of more tractable animal models.

Dogs suffer from the same range of diseases than we do but the genetic complexity of those diseases is reduced within dog breeds when compared to humans due to the history of the dog population. Consequently not only the number of genetic markers needed is lower but also the number of individuals requested. A two-stage approach, combining within-breed and subsequent between-breed analyses, has been demonstrated to be successful for a precise localization of genetic factors in dogs (Karlsson et al, Nat Genet. 2007. 39:1321-8.)

The main goal of LUPA is to identify genes and mutations that account for the high incidence of certain diseases in specific dog breeds. The culprit genes are identified by genome-wide association (GWA) studies using panels of SNP markers covering the entire dog genome. Marker allele frequencies are compared between cohorts of affected individuals (cases) and cohorts of properly matched controls. The project is divided into ~20 different diseases (sub-workpackages). Each disease shows evidence for an inherited component. The phenotype is rigorously defined and relevant for human health. The experimental design corresponds to a two-stage approach as described upper. The diseases are grouped into 5 pathological themes: cancers, cardiovascular disorders, inflammatory disorders, neurological disorders and miscellaneous monogenic disorders. Altogether, the LUPA project aims at performing genome-wide SNP scans on more than 10,000 dogs.

Each sub-workpackage comprises four distinct phases: - Sample collection and phenotyping (mostly during the first two years of the project) - Genome-wide SNP genotyping and association analysis (GWA) - Fine-mapping to identify the smallest possible associated region - Mutational screen and molecular biology for functional follow-up of candidate mutations. Twenty veterinary clinics in 12 European countries are working together to collect DNA samples required for the different cohorts. Collection and phenotypic characterization of most cohorts is a huge task and has lasted for 24 to 30 months, some samples collection is still ongoing. During the first years advertisement was very important in order to further involve kennel clubs, breeders, private veterinary practices and owners in the cohorts collection step.

Project results:

Since the start of the project 2,150 samples have been genotyped using the 50K Affymetrix array and 5,500 samples using the new 170K Illumina array. All genotypes are stored in the LUPA central database available for analysis by the collaborating centres. When requested the support of a dedicated statistical genetics platforms is offered. Promising results are coming out with 2 monogenic diseases deciphered and identification of new genes involved in similar human diseases. For complex disorders several dog genomic regions are significantly associated with different forms of epilepsy, cancers, cardiovascular and inflammatory disorders. Further characterization and fine-mapping of associated loci has been initiated with a special focus on candidate genes present within each of those loci.

Potential impact:

LUPA is already providing new insights into the pathogenesis of some common human diseases. In addition, the project has the potential to have a major impact on the future of veterinary medicine in Europe.

Project website: http://www.eurolupa.org/