Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants?
OBJECTIVE
According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci.


METHODS
We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F (ST)) for 17 type 2 diabetes and 13 obesity loci.


RESULTS
We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F (ST) for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date.


CONCLUSIONS
Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues.
Southam
L
L
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Soranzo
N
N
Montgomery
S B
SB
Frayling
T M
TM
McCarthy
M I
MI
Barroso
I
I
Zeggini
E
E
D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D005523:Food Supply; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009765:Obesity / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012307:Risk Factors; D012641:Selection, Genetic