Admixture mapping of 15,280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X

Abstract

The prevalence of obesity (body mass index (BMI) > or =30 kg/m(2)) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6x10(-7)). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.

Figure 1. Scatter-plots of BMI vs. the estimated percentage of European ancestry.

(A) Percentage of European ancestry was estimated based on the autosomes. (B) Percentage of European ancestry was estimated based on chromosome X. Data are plotted using 20% of the samples (selected at random) for better visualization.

Figure 2. The dichotomous admixture scans for genetic loci affecting BMI.

The locus-specific LOD score (red line) and the case-control Z score (blue gray line) are shown for Run 1 in Table 2: BMI was adjusted for age, age-squared, sex and studies. A signal at genome-wide significant level (locus-specific LOD = 5.94) was detected at Xq25. The Xq25 peak was also supported by the case-control statistic (Z score = −3.94, P = 8.1×10⁻⁵). Another peak on chromosome X was observed at Xq13.1 (locus-specific LOD = 2.22). Although its LOD score did not reach statistical significance, it had the largest magnitude case-control Z score of −4.62 (P = 3.8×10⁻⁶) anywhere in the genome. Moreover, we observed an admixture signal at 5q13.3 (locus-specific LOD = 2.48), which did not reach significance, but had the strongest positive case-control Z score across the genome (Z score = 4.03, P = 5.6×10⁻⁵).

Figure 3. The quantitative admixture scans for genetic loci affecting BMI.

The quantitative admixture scans identified an association peak at 5q13.3 with a locus-specific LOD score of 6.27 and a genome-wide score of 3.46, both reaching the thresholds for genome-wide significance.