Keri Monda, Kari North, Christopher Haiman and colleagues report a meta-analysis of GWAS for body mass index that is composed of 39,144 individuals of African ancestry, followed by further genotyping in 32,268 individuals of African ancestry. The study also includes analysis of publicly available data from the GIANT consortium of ~124,000 individuals of European ancestry. The paper reports evidence for two new loci near GALNT10 and MIR148A. Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10−11) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10−8). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10−7), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10⁻⁶ were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10⁻⁸ for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10⁻⁸ for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10⁻⁸; RREB1: p = 5.7×10⁻⁸). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity. Central obesity is a marker of body fat distribution and is known to have a genetic underpinning. Few studies have reported genome-wide association study (GWAS) results among individuals of predominantly African ancestry (AA). We performed a collaborative meta-analysis in order to identify genetic loci associated with body fat distribution in AA individuals using waist circumference (WC) and waist to hip ratio (WHR) as measures of fat distribution, with and without adjustment for body mass index (BMI). We uncovered 2 genetic loci potentially associated with fat distribution: LHX2 in association with WC-adjusted-for-BMI and at RREB1 for WHR-adjusted-for-BMI. Six of fourteen previously reported loci for waist in EA populations were significant in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). These findings reinforce the concept that there are loci for body fat distribution that are independent of generalized adiposity.

Recent pooled analyses show an increased risk of death with increasing levels of the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 25.0 or higher in populations of European ancestry, a weaker association among East Asians, and no association of an increased BMI with an increased risk of death among South Asians. The limited data available on blacks indicate that the risk of death is increased only at very high levels of BMI (≥35.0). We prospectively assessed the relation of both BMI and waist circumference to the risk of death among 51,695 black women with no history of cancer or cardiovascular disease who were 21 to 69 years of age at study enrollment. Our analysis was based on follow-up data from 1995 through 2008 in the Black Women's Health Study. Multivariable proportional-hazards models were used to estimate hazard ratios and 95% confidence intervals. Of 1773 deaths identified during follow-up, 770 occurred among 33,916 women who had never smoked. Among nonsmokers, the risk of death was lowest for a BMI of 20.0 to 24.9. For a BMI above this range, the risk of death increased as the BMI increased. With a BMI of 22.5 to 24.9 as the reference category, multivariable-adjusted hazard ratios were 1.12 (95% confidence interval [CI], 0.87 to 1.44) for a BMI of 25.0 to 27.4, 1.31 (95% CI, 1.01 to 1.72) for a BMI of 27.5 to 29.9, 1.27 (95% CI, 0.99 to 1.64) for a BMI of 30.0 to 34.9, 1.51 (95% CI, 1.13 to 2.02) for a BMI of 35.0 to 39.9, and 2.19 (95% CI, 1.62 to 2.95) for a BMI of 40.0 to 49.9 (P<0.001 for trend). A large waist circumference was associated with an increased risk of death from any cause among women with a BMI of less than 30.0. The risk of death from any cause among black women increased with an increasing BMI of 25.0 or higher, which is similar to the pattern observed among whites. Waist circumference appeared to be associated with an increased risk of death only among nonobese women. (Funded by the National Cancer Institute.)

Background: Most genome-wide association studies (GWAS) have been carried out in European ancestry populations; no risk variants for breast cancer have been identified solely from African ancestry GWAS data. Few GWAS hits have replicated in African ancestry populations. Methods: In a nested case–control study of breast cancer in the Black Women's Health Study (1,199 cases/1,948 controls), we evaluated index single-nucleotide polymorphisms (SNP) in 21 loci from GWAS of European or Asian ancestry populations, overall, in subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status (ER+/PR+, n = 336; ER−/PR−, n = 229), and in triple-negative breast cancer (TNBC, N = 81). To evaluate the contribution of genetic factors to population differences in breast cancer subtype, we also examined global percent African ancestry. Results: Index SNPs in five loci were replicated, including three associated with ER−/PR− breast cancer (TERT rs10069690 in 5p15.33, rs704010 in 10q22.3, and rs8170 in 19p13.11): per allele ORs were 1.29 [95% confidence interval (CI) 1.04–1.59], P = 0.02, 1.52 (95% CI 1.12–2.08), P = 0.01, and 1.30 (95% CI 1.01–1.68), P = 0.04, respectively. Stronger associations were observed for TNBC. Furthermore, cases in the highest quintile of percent African ancestry were three times more likely to have TNBC than ER+/PR+ cancer. Conclusions: These findings provide the first confirmation of the TNBC SNP rs8170 in an African ancestry population, and independent confirmation of the TERT ER− SNP. Furthermore, the risk of developing ER− breast cancer, particularly TNBC, increased with increasing proportion of global African ancestry. Impact: The findings illustrate the importance of genetic factors in the disproportionately high occurrence of TNBC in African American women. Cancer Epidemiol Biomarkers Prev; 22(1); 127–34. ©2012 AACR.