African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three U.S. population cohorts

Abstract

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13-1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6 × 10(-6)). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk.

Figure 1. Odds ratio of type 2 diabetes by African ancestry in the ARIC and JHS studies.

Odds ratios were based on restricted cubic splines with knots at the 5th, 35th, 65th and 95th percentiles. The reference was set at the 5th percentile (63.8%) of the African ancestry distribution. The odds ratio was adjusted for age, sex and study (shot-dashed line), and further adjusted for socioeconomic status, including education level, family income, and occupations (long-dashed line). The solid line indicates the odds ratio adjusted for age, sex, study, socioeconomic status, and BMI; the shaded area represents its 95% confidence intervals.

Figure 2. Admixture scans for genetic loci of type 2 diabetes in African Americans.

Locus-genome statistic (LOD score, red line) and case-control statistic (Z score, blue gray line) are shown. A signal was detected at 12p13.31 with a locus-specific LOD score of 4.0, just reaching the threshold of 4 for suggestiveness. The 12p13.31 peak was also supported by the case-control statistic (Z score = −4.2, nominal P = 3.3×10⁻⁵). The second strongest admixture signal was observed on the same chromosome at 12q13.13 (locus-specific LOD = 3.8). There was also an admixture peak at 13q14.3 that did not reach genome-wide significance by the locus-genome statistic (locus-specific LOD = 1.1), but that had the largest magnitude case-control Z score anywhere in the genome (Z score = 4.5, nominal P = 6.6×10⁻⁶).