We have conducted a large-scale admixture genetic analysis in more than 7,000 African Americans to determine the association of African ancestry with type 2 diabetes and to map susceptibility loci for type 2 diabetes. With 2,373 cases with type 2 diabetes and 4,648 controls, we found that greater African ancestry was significantly associated with type 2 diabetes and HbA1c values even after adjustment for BMI and markers of SES, including education, income, and occupation. Despite the significant association between greater African ancestry and type 2 diabetes, no major locus for diabetes could be detected by our admixture scans, using the more powerful locus-genome statistic.
Our results show that there is 30% to 40% increase in odds of type 2 diabetes among participants in the highest (>87.5%) vs. the lowest (<80.5%) tertile of African ancestry, even after adjustment for measures of SES and/or BMI. Our restricted cubic spline models also support this extrapolation, implying that genetic ancestry is a major independent determinant of the observed disparity in diabetes risk between the two ethnic groups. We note that in our study, markers of SES (education, income, and occupation) account for only a modest proportion (~22%) of the excess odds of type 2 diabetes due to ancestry. The results contrast to previous findings in Hispanic Americans 
, where the association between their non-European ancestry and type 2 diabetes is also significant, but where SES appears to be a much greater confounder, as adjustment for it significantly attenuated the association signal. It is also worth noting that the previous study had less power than our study as it used fewer individuals and fewer ancestry informative markers 
Insulin resistance and β–cell dysfunction are known to be major factors in the pathogenesis of type 2 diabetes. Evidence from epidemiological studies indicates that African Americans tend to be more insulin resistant and have greater insulin responses to glucose than European Americans 
. Our results showed a positive (but statistically non-significant) correlation between African ancestry and HOMA-IR, in line with one earlier study that demonstrated that children with greater African ancestry had lower insulin sensitivity and a higher acute insulin response 
. In genome-wide scans to date, the majority of the genetic variants for type 2 diabetes identified in European-derived populations appeared to be related to impaired insulin secretion 
, while only IRS1
has been unequivocally associated with insulin resistance 
. However, a limitation is that these studies have been carried out largely in Europeans. It will be interesting to explore whether the loci associated to type 2 diabetes in African Americans are also associated with impaired insulin secretion, once genome-wide association studies of sufficient power are carried out.
Previous genome-wide scans for type 2 diabetes in African-descent populations have been extremely limited, and there has only been one study using admixture-based approaches. In the GENNID (Genetic of NIDDM) Study, using markers from a linkage panel in 1,450 African Americans, the strongest admixture association was found on chromosome 12 (90 cM), but no loci achieved genome-wide significance 
. In our large population with a high number of ancestry informative markers, the two most interestingly loci using were at 12p13.31 and 13q14.3. While neither of these loci was significant by our locus-genome statistic which has the most statistical power, the case-control Z score at both loci exceeded the threshold for genome-wide significance, which makes these loci of interest for further study. An attractive candidate gene at the 12p13.31 locus is glyceraldehyde-3-phosphate dehydrogenase (GAPDH
), which is a key enzyme in the glycolytic pathway and is known to affect insulin receptor signaling 
. The 12p13.31 locus has been found to be associated with type 1 diabetes in previous genome-wide association studies in European-derived populations 
, but neither of the two loci has been associated with type 2 diabetes in either African Americans or Europeans.
An interesting feature of our admixture scanning results is that diabetes risk at 12p13.31 and 13q14.3 were associated with ancestry in opposite directions. At 13q14.3, greater European ancestry is associated with a higher risk of diabetes, opposite to the direction of the overall epidemiological association, a phenomenon that we documented for the first time in a study of obesity loci 
. These two loci, together with the other modest admixture signals on chromosome 12 and 1, and the absence of significant signals in locus-genome statistic elsewhere in the genome, suggest no evidence for a large genetic effect for type 2 diabetes that is racially/ethnically differentiated, such as that at the MYH9
locus for non-diabetic end stage renal disease 
. Thus multiple loci modest effects may, in aggregate, explain the apparent difference in genetic risk for type 2 diabetes between African Americans and European Americans.
Our study has important limitations. Despite the fact that our study size far exceeds previous genome scans for type 2 diabetes risk loci in African Americans, statistical power remains an important concern. We carried out simulation studies to examine the power of our study to detect a genomic locus of elevated African ancestry 
. With a total of 2,373 diabetic cases, we expect to have 80% power to detect a 1.8-fold increased risk of type 2 diabetes per allele for alleles that are ancestry informative between Europeans and West Africans but less power for weaker ORs. A second limitation is that we used BMI as the only measure of adiposity. Including some other measure, such as waist circumference, might further attenuate the diabetes-ancestry association. In our previous analysis, however, we found that BMI, but not waist circumference, was significantly correlated with genetic ancestry after adjustment for SES 
, suggesting that confounding by waist circumference would have a minimal effect on results. Third, as in many studies involving SES, we were not able to fully assess SES and made inferences about SES based on education, income, and occupation, which, although are strong markers for SES, are still imperfect 
. For example, SES may also be correlated with other diabetes risk factors, such as diet and life-style, and historical socioeconomic factors could in theory interact in complex ways with African ancestry to influence diabetes risk, making the associations among them even more complicated.
In summary, in community-based populations with more than 7,000 African Americans, we found that genetic ancestry is significant associated with type 2 diabetes above and beyond the effects of markers of SES, and we detected several suggestive loci that may harbor genetic variants modulating diabetes risk. These results suggest that in African Americans, genetic ancestry has a significant effect on the risk of type 2 diabetes that are independent of the contribution of SES, but that no single locus with a major effect explains a large portion of the observed disparity in diabetes risk between African Americans and European Americans. In addition, they suggest that genetic measured African ancestry contributes to the risk of type 2 diabetes via both genetic and non-genetic pathways. The effect of ancestry on any individual locus in the genome is likely to be modest, but in aggregate, differences in ancestry may contribute substantially to the observed ethnic disparity in risk of type 2 diabetes.