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Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.

Original publication




Journal article


Nature genetics

Publication Date





76 - 80


Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA.


Humans, Diabetes Mellitus, Type 2, Cholesterol, Blood Glucose, Lipoproteins, HDL, Alanine, Proline, Receptors, Cytoplasmic and Nuclear, Transcription Factors, Body Mass Index, Risk Factors, Fathers, Mothers, Age of Onset, Blood Pressure, Genotype, Linkage Disequilibrium, Phenotype, Polymorphism, Genetic, Alleles, Models, Genetic, Adult, Aged, Middle Aged, Family Health, Female, Male