ABSTRACT
The identification of genes for complex human disease, such as obesity, has proved to be a challenge with so far limited success. Genetic studies using microsatellite markers have successfully identified genes for monogenic diseases, especially obesity syndrome like Bardet-Biedl diseases as described in Section 5, but have been notably poor in identifying genes for common obesity forms or obesity related complex traits. The genome-wide resolution that can be reasonably achieved using microsatellites is relatively low ranging between 10 centiMorgans and 5 centiMorgans. Higher resolutions can be achieved using high density single-nucleotidepolymorphism (SNP) chips for linkage mapping (1,2). To widely explore the genome of obese subjects, large DNA banks have been constituted in different populations through out the world: individuals and families with extreme obesity occurring during adulthood or childhood (European and American studies), cohorts issued from the general population (Quebec family study), and in particular groups (Pima Indians, Mexican Americans, African Americans and Amish) (3). Recently a population from the Pacific Island of Kosrae was also explored (4). The genome-wide scan task is performed without pre-conceptions about the functions of the genes and aims to identify known or unknown genes pre-disposing to obesity. Then molecular tools enable the newly identified genes to be positioned and eventually cloned. It is sometimes arduous to find the exact causative gene when genomic linked regions encompass thousand of bases and sometimes hundred of genes. The results of these genetic studies are reported each year in the international journal “Obesity Research” (4). The global picture of chromosomal regions linked to obesity illustrates the complexity of this multifactorial disease. At least, sixty-one genome-wide scans have been conducted and more than 250 regions, located on nearly all the chromosomes as shown on Figure 1, have been linked to different obesity related phenotypes such as fat mass, the distribution of adipose tissue, the occurrence of a metabolic syndrome, resting energy expenditure, energy and macronutrient intake, weight variation, the levels of circulating leptin, and insulin among other phenotypes (all references in (4). Some loci may be more specific for morbid obesity or childhood obesity (5,6) as detailed in Chapter 6.3. Interactions between chromosomal regions such as on chromosome 10 and 20 and
between chromosome 13 and 2 (i.e. epistasis) were also shown. These regions may interact to influence extreme obesity (7,8). Candidate genes were also found in these regions linked with obesity phenotypes.
