New Candidate Obesity Genes

Modern molecular genetics is a fast-growing tool to understand different diseases and clinical conditions. Understanding genetic basis of obesity is yet to be achieved, although this field has been increasing tremendously in recent years. Several single-gene mutations have been linked to obesity in animal models but not in humans because it is considerably more complicated. It is expected that obesity arise from the interactions of multiple genes which makes the search for obesity genes a real challenge. Anonymous major genes accounting for as much as 40 percent of the variation in body weight and the same percentage of the variation in fat mass have been reported in addition to major genes influencing adipose tissue distribution.

Identifying the genetic determinants influencing obesity development needs pulling resources and knowledge from different laboratories around the world comprising both academic and industrial partners. It is important to know that the association of a gene with complex traits indicates a possible causative gene, but it should be clear that no single SNP (single nucleotide polymorphism) could be linked to obesity alone but a combination of different genes exposes an individual to develop obesity. It is also clear from several studies that certain SNPs may work as a protecting gene against obesity. Transgenic mice molecular biology technique, quantitative traits loci (QTL), gene mapping, and chromosomal scanning has been widely used to look for obesity candidate genes. Gene linkage analysis can be performed with candidate gene markers or with a variety of other polymorphic markers, such as microsatellites. Evidence for linkage becomes more apparent as the marker loci get closer to the true locus that cosegregates with the phenotype. The bulk of the ongoing research focuses on the molecular mechanisms of appetite and satiety regulation, energy metabolism, nutrient partitioning, and adipose cell differentiation and enlargement.

As of early 2007, several obesity candidate gene have been reported in the form of single-gene mutation and many expressed genes resulted in a phenotype that affect body weight and adiposity. The numbers of QTLs human obesity-related phenotypes are increasing which widen the genomic regions exploration. Recently, there have been many studies reporting associations between DNA sequence variations and obesity phenotypes.

Different international laboratories carry out large-scale genomic studies with an aim to look for geneto-environmental determinants susceptibility to obesity development. The new approach described by Herbert et al. will provide a template for future association studies. Using a multistage design, without sacrificing genome-wide significance, the authors selected the top 10 SNPs for further analysis, and only one SNP variant near the INSIG2 gene was associated with obesity.

The human obesity gene map 2005 update presents the latest 12th update of the human obesity gene map, which incorporates published results up to the end of the year 2005. In that report, 176 human obesity cases due to single-gene mutations in 11 different genes and 50 loci related to Mendelian syndromes relevant to human obesity have been mapped. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. The electronic version of the map with links for useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

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