Missing heritability and GWAS utility.

The environment is largely responsible for differences in BMI between populations; genetics is largely responsible for differences in BMI within populations. Evidences in support of the environmental effect are many. The prevalence of obesity differs greatly between countries, even among developed countries (1). On a smaller scale, differences in the “built environment” within a city are associated with differences in BMI. In New York City a greater density of bus and subway stops and greater variety in uses of land within a neighborhood are associated with lower BMIs (2). Closely genetically related populations living in different environments differ considerably in average BMI (3). The environment clearly can be more or less obesegenic. But there is strong evidence that within a population the variance in BMI is largely genetically determined. The weight of adoptees correlates better with the BMI of their biologic parents than with that of their adoptive parents (4). Twin studies indicate that about two-thirds of the variance in BMI is attributable to additive genetic factors (5). The most convincing study of the heritability of BMI in twins was that of Stunkard and colleagues, who studied 93 adult pairs of monozygotic twins who had been separated as young children and reared apart (6). These authors similarly estimated that about two-thirds of the variance in BMI was due to genetic factors. What are these genetic factors? Two different experimental approaches have been used to identify obesity susceptibility genes in humans: a candidate gene approach and an agnostic method using single-nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS). Candidate genes have been selected to be screened for variants associated with obesity based on the physiology and molecular mechanisms of energy homeostasis in experimental animals. Very few obese humans have causative variants in genes thought to be the major constituents of this homeostatic system (7). The one exception is the melanocortin 4 receptor (MC4R). About two and a half percent of severely obese individuals have causative variants in this gene (8). These variants are associated with obesity largely due to increased food intake but also due to reduced energy expenditure (9). GWASs are the most commonly used agnostic approach to identify susceptibility genes for common disease, including obesity. These have been done in populations of European descent and used ~350,000 SNPs, covering more than 75% of the genome (10,11). The two major findings were common noncoding SNPs in an intron of the FTO gene and a common SNP within a presumed regularly site 188 kb downstream of the MC4R gene. The additive genetic effect of these polymorphisms in a population of ~77,000 adults was a difference in BMI of 1.17kg/m2 between the compound homozygotes for the risk alleles (1% of the population) vs. the compound homozygotes for the nonrisk alleles (19% of the population). These two common variants in FTO and MC4R account for less than 2% of the variance in adult BMI. The combined results of the candidate gene and GWAS approach account for very little of the variance in BMI that is heritable.