Both environmental and genetic factors are involved in the onset and progression of weight gain [4]. Excess caloric intake and the tendency towards a more sedentary lifestyle are certainly to blame for the increased prevalence of obesity, but individuals exposed to the same environmental pressures have different levels of vulnerability. Indeed, genetic epidemiologic studies, such as twin studies [5] and adoption studies [6], have implicated genetic factors in the susceptibility to obesity. These studies have shown that genetic factors account for 40-70% of the population variation in BMI and that the heritability of obesity increases with its severity [7]. Emphasis has therefore now shifted from the question of whether human obesity has a genetic component to how many and which genetic variants underlie this susceptibility [8,9].

In 2008, reports of the first genome-wide association studies (GWASs) for obesity revealed previously unreported associations with common variants near the fat mass and obesity-associated gene FTO [11], a gene with a yet unknown function, and near the melanocortin 4 receptor (MC4R) gene [12], in which multiple rare variants had previously been shown to cause, in aggregate, 2-4% of severe obesity (BMI ≥ 40 kg/m²) cases in humans [13,14]. These findings were replicated across several populations, but the common alleles at these two loci had only a modest effect on BMI (0.2-0.4 kg/m²), suggesting that additional common variants could account for a significant fraction of the inherited BMI population variation.

By combining extremely large samples of GWASs, recent reports now provide us with a more comprehensive view of the extent to which common variants are associated with obesity [15,16]. Investigators of the Genetic Investigation of Anthropometric Traits (GIANT) consortium conducted a meta-analysis of GWASs from a total of 32,387 subjects of European ancestry in 15 cohorts for association with BMI [16]. The strongest signals from 35 variants were used for follow-up in 14 additional cohorts with over 59,000 subjects of European ancestry. In parallel, a group at deCODE Genetics performed a GWAS with single nucleotide polymorphisms (SNPs) typed in over 30,000 individuals of mixed descent (predominantly Icelandic, but also Dutch, European American, African American and Scandinavian) in search of polymorphic variants that affect variation in two common measures of obesity, weight and BMI [15]. The strongest signals from 43 variants were then tested for association in 5,586 Danish individuals and compared in silico with the results of the GIANT consortium [15].

Both studies confirmed the association of BMI with variants at the FTO and MC4R genes and identified six and nine novel loci, respectively, at which variants were associated with BMI and/or weight, four of which (NEGR1, TMEM18, SH2B1 and KCTD15) were common to both studies (Table ​(Table11).

Many of the new loci, in particular those found by the GIANT consortium, are located near genes that are highly expressed in the central nervous system, several in the hypothalamus, possibly emphasizing, as in rare monogenic forms of obesity, the role of the hypothalamus in the predisposition to obesity. Of course, this conclusion is preliminary, as the actual causative variants, which remain to be identified by fine mapping at each of these loci, may affect other genes in these regions.

Both the GIANT and deCODE studies also acknowledge that their results lend credence to the hypothesis that rare or unique alleles with strong or intermediate effects could account for the majority of one individual's predisposition to obesity. Testing this hypothesis, and finding genes for which this is the case, will require comparative sequencing to search for an increase in the aggregate number of rare variants at each locus in cases versus controls. The largest pioneering study yet to test this hypothesis sequenced the entire coding region of 58 candidate genes in 379 extremely obese and 378 extremely lean adults [19]. The authors found an increase in unique non-synonymous variations in severely obese individuals, specifically in a subset of genes expressed in the central nervous system and for which the corresponding mouse phenotype was suggestive of a role in obesity. Searching for such loci systematically at a genome-wide level will require extremely large-scale sequencing, for which the technology is currently being developed and which will present us with new statistical challenges and methodological difficulties pertaining, for example, to the functional study and classification of identified variants.