Hundreds of studies in the past 15 years have suggested a positive association of common variants in a large number of candidate genes with obesity or obesity-related phenotypes. As for several other common diseases, most of these studies failed to be replicated, being limited by their insufficient sample size and by stratification and multiple testing issues [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
], 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
]. 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
]. 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 ).
Summary of loci associated with variation in adult BMI in two large GWASs
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.
In both studies, the allelic odds ratio for being obese (BMI >30 kg/m2
) remained greatest with the FTO
variant (Table ), with odds ratios of 1.03-1.25 [16
] and 1.07-1.27 [15
]. All of the variants identified are relatively common, and their combined effect explains only a small percentage of the variation in weight and BMI. The GIANT consortium examined the combined impact of the associated variants on BMI. They weighted the number of BMI-increasing alleles by their relative effect size and calculated a genotype score for each individual. They found that individuals that have 13 or more BMI-increasing alleles (representing 1.2% of the sample) are only 0.59 kg/m2
heavier than the average individual in their study. In addition, when the GIANT consortium removed the associated loci from the analysis, they no longer identified an excess of p
-values smaller than what is expected by chance [16
]. The authors rightly argue that common variants with even smaller effects may not have been detected and could still be found with even larger sample sizes. However, as these effects will be small, the data from both studies suggest that most of the heritability of BMI captured by common variants has been accounted for.