CEPH - Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain

Europe is the oldest continent and is rapidly aging. The aim of the IP GEHA is to identify genes involved in healthy aging and longevity, allowing individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age-related diseases. To achieve this aim a coherent, tightly integrated program of research that unites demographers, geriatricians geneticists, genetic epidemiologists, molecular biologists, bioinfomaticians and statisticians has been set up. The genetic analysis will be performed by 8 high throughput platforms, within the framework of a centralized database. The working plan of this IP is to: i) collect an unprecedented number (2550) of long-lived (90+) sibpairs from 10 European countries; ii) perform a genome scan by microsatellites in all the sibpairs (a total of 5100 individuals) iii) refine the regions identified by the genome scan by a linkage disequilibrium (LD) mapping using SNPs in cases (i.e. the 2550 probands of the sibpairs) and in 2550 younger controls who will also be recruited, followed by positional cloning and mutational analysis. Three regions in chromosome 4 (D2S1564), 11(11.p15.5) and 19 (around APOE gene) suggested to be involved in aging and longevity in previous studies, will be investigated for their LD block structure in CEPH families and then by an economic number of SNPs in the entire collection of recruited people. All the recruited people will also be genotyped mitochondrial DNA haplogroups and mutations known to play a major role in aging and longevity. Additional advanced approaches (bioinformatics, advanced statistics, mathematical modelling, functional genomics and proteomics, molecular genetics) are envisaged to identify the gene variant(s) of interest. The experimental design will also allow i) to identify gender-specific genes involved in healthy aging and longevity in women and men; ii) to develop mathematical and statistical model.

Knowledge of the extent of linkage disequilibrium (LD) and its variation across the genome is required for the efficient and systematic implementation of mapping functional polymorphisms implicated in common, complex disorders.. The overall goal of this project is to determine extent and variation of LD in the genome of the general population of European populations. DNA from population samples of unrelated individuals will be typed with some 250 micro satellites and SNPs in nine genomic regions and the entire chromosome 22 (C22). The extent of LD will be measured for each region and for C22, and will be compared across populations. The across-population variability of extent of LD will be interpreted by the demographic history of each population. Each genome region will be compared for extent of LD across chromosomes and between populations. Inherent genome, sequence-related characteristics will be used to interpret regional variability. Regions harbouring genes implicated in complex disorders will also be studied. Frequencies phaplotypes extending across each genomic region will be estimated for each population. Computer programs used for data analysis and all DNA types generated in this project will be available to the public at the completion of this project.

Knowledge of the extent of linkage disequilibrium (LD) and its variation across the genome is required for the efficient and systematic implementation of mapping functional polymorphisms implicated in common, complex disorders.. The overall goal of this project is to determine extent and variation of LD in the genome of the general population of European populations. DNA from population samples of unrelated individuals will be typed with some 250 micro satellites and SNPs in nine genomic regions and the entire chromosome 22 (C22). The extent of LD will be measured for each region and for C22, and will be compared across populations. The across-population variability of extent of LD will be interpreted by the demographic history of each population. Each genome region will be compared for extent of LD across chromosomes and between populations. Inherent genome, sequence-related characteristics will be used to interpret regional variability. Regions harbouring genes implicated in complex disorders will also be studied. Frequencies phaplotypes extending across each genomic region will be estimated for each population. Computer programs used for data analysis and all DNA types generated in this project will be available to the public at the completion of this project.

Inflammatory bowel diseases (IBD), including Crohn's Disease (CD) and Ulcerative Colitis (UC) are common diseases occurring in young adults. They are frequently complicated by denutrition, mutilating surgery and cancerisation of the chronic inflammatory lesions. In the absence of known aetiology, their treatment is symptomatic, based on surgery, anti-inflammatory drugs and immunosupressor agents. However, these therapies are limited by their major side effects. A genetic predisposition to IBD, compatible with a multifactorial model of inheritance, is well established and a genome-wide search, in order to localise predisposing genes for IBD, was recently initiated in Europe. It enabled the provisional assignment of linkage to the pericentromeric region of chromosome 16 of a first CD susceptibility locus named IBD1. The identification of IBD susceptibility genes would be a key step in the understanding of the fundamental causes playing an etiologic role in IBD. However, for diseases with a complex mode of inheritance, a large number of families is required for such genetic studies. They cannot be found in a single European country. A collaborative network in order to recruit and characterise a large number of IBD families is a necessary prerequisite. The major goals of this project are to foster the interaction of fundamental and clinical research around the genetics of IBD and to provide a powerful tool for researchers in establishing centralised clinical and biological databases of IBD families. The objectives will be reached under the following interrelated tasks: (i) the identification and recruitment of IBD families using harmonised criteria, (ii) the creation of a centralised computer database containing clinical data and the development of a repository of biological material from IBD patients, (iii) the information on genetics of IBD and promotion of genetic studies. The recruitment of multiplex IBD families will help to reach the following objectives: 1) to localise more precisely the susceptibility gene within chromosome 16; 2) to identify additional susceptibility loci; 3) to investigate which, if any, loci involved in CD may also be relevant to UC; 4) to establish a more precise genetic model for the genetic susceptibility to IBD which would take into account the contribution of each identified locus and their possible interactions; 5) to estimate the relative risk of the different combinations of the predisposing alleles. It is expected that our knowledge concerning the genetics of IBD will further help to provide the bases for new development including the research and the validation of molecular diagnostic tools, the identification of defined subgroups of patients who could benefit of specific treatment or could be targeted for preventive actions, the understanding of the pathophysiology of the disease and the development of new approaches for therapeutic research.

Inflammatory bowel diseases (IBD), including Crohn's Disease (CD) and Ulcerative Colitis (UC) are common diseases occurring in young adults. They are frequently complicated by denutrition, mutilating surgery and cancerisation of the chronic inflammatory lesions. In the absence of known aetiology, their treatment is symptomatic, based on surgery, anti-inflammatory drugs and immunosupressor agents. However, these therapies are limited by their major side effects. A genetic predisposition to IBD, compatible with a multifactorial model of inheritance, is well established and a genome-wide search, in order to localise predisposing genes for IBD, was recently initiated in Europe. It enabled the provisional assignment of linkage to the pericentromeric region of chromosome 16 of a first CD susceptibility locus named IBD1. The identification of IBD susceptibility genes would be a key step in the understanding of the fundamental causes playing an etiologic role in IBD. However, for diseases with a complex mode of inheritance, a large number of families is required for such genetic studies. They cannot be found in a single European country. A collaborative network in order to recruit and characterise a large number of IBD families is a necessary prerequisite. The major goals of this project are to foster the interaction of fundamental and clinical research around the genetics of IBD and to provide a powerful tool for researchers in establishing centralised clinical and biological databases of IBD families. The objectives will be reached under the following interrelated tasks: (i) the identification and recruitment of IBD families using harmonised criteria, (ii) the creation of a centralised computer database containing clinical data and the development of a repository of biological material from IBD patients, (iii) the information on genetics of IBD and promotion of genetic studies. The recruitment of multiplex IBD families will help to reach the following objectives: 1) to localise more precisely the susceptibility gene within chromosome 16; 2) to identify additional susceptibility loci; 3) to investigate which, if any, loci involved in CD may also be relevant to UC; 4) to establish a more precise genetic model for the genetic susceptibility to IBD which would take into account the contribution of each identified locus and their possible interactions; 5) to estimate the relative risk of the different combinations of the predisposing alleles. It is expected that our knowledge concerning the genetics of IBD will further help to provide the bases for new development including the research and the validation of molecular diagnostic tools, the identification of defined subgroups of patients who could benefit of specific treatment or could be targeted for preventive actions, the understanding of the pathophysiology of the disease and the development of new approaches for therapeutic research.