Analysis of Positive Selection at Single Nucleotide Polymorphisms Associated with Body Mass Index Does Not Support the "Thrifty Gene" Hypothesis.

The "thrifty gene hypothesis" suggests genetic susceptibility to obesity arises because of positive selection for alleles that favored fat deposition and survival during famines. We used public domain data to locate signatures of positive selection based on derived allele frequency, genetic diversity, long haplotypes, and differences between populations at SNPs identified in genome-wide association studies (GWASs) for BMI. We used SNPs near the lactase (LCT), SLC24A5, and SLC45A2 genes as positive controls and 120 randomly selected SNPs as negative controls. We found evidence for positive selection (p < 0.05) at nine out of 115 BMI SNPs. However, five of these involved positive selection for the protective allele (i.e., for leanness). The widespread absence of signatures of positive selection, combined with selection favoring leanness at some alleles, does not support the suggestion that obesity provided a selective advantage to survive famines, or any other selective advantage.