Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using 14C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10−8): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10−9), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10−32) and SLC22A12 (P= 2.1 × 10−10). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta −1.19 mg/dl, P= 2.7 × 10−16). 14C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

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.

Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 × 10−6 and 3.61 × 10−6 in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.

Background

Electrocardiographic QT interval prolongation is a risk factor for sudden cardiac death (SCD) and drug-induced arrhythmia. The clinical correlates and heritability of QT interval duration in African Americans have not been well studied despite their higher risk for SCD compared to non-Hispanic whites. We sought to investigate potential correlates of the QT interval and estimate its heritability in the Jackson Heart Study (JHS).

Methods and Results

The JHS comprises a sample of African Americans residing in Jackson, Mississippi, of whom 5302 individuals with data at the baseline examination were available for study. JHS participants on QT-altering medications, with bundle branch block, paced rhythm, atrial fibrillation/flutter or other arrhythmias were excluded resulting in a sample of 4660 individuals eligible for analyses. The relation between QT and potential covariates was tested using multivariable stepwise linear regression. Heritability was estimated using SOLAR in a subset of 1297 JHS participants in 292 families; the remaining sample included unrelated individuals. In stepwise multivariable linear regression analysis, covariates significantly associated with QT interval duration included RR interval, female sex, QRS duration, age, lower potassium, hypertension, body mass index, coronary heart disease, diuretic use, and Sokolow-Lyon voltage (p ≤ 0.01 for all). The heritability of QT interval duration in age-, sex- and RR-interval-adjusted and fully-adjusted models was 0.41 (SE 0.07) and 0.40 (SE 0.07, p<10−11 for both), respectively.

Conclusions

There is substantial heritability of adjusted QT interval in African Americans supporting the need for further investigation to identify its genetic determinants.

Background

Chronic kidney disease (CKD) leads to End Stage Renal Disease (ESRD) and is a growing epidemic throughout the world. In the United States, African Americans have an incidence of ESRD four times that of Whites.

Study Design

Cross Sectional to examine the prevalence and awareness of CKD in African Americans

Setting & Participants

Observational Cohort in the Jackson Heart Study (JHS)

Predictor

CKD was defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2, presence of albuminuria, or being on dialysis

Outcomes and Measurements

Data from the Jackson Heart Study (JHS) were analyzed. Medical history including disease awareness and drug therapy, anthropometric measurements, serum, and urine samples were obtained from JHS participants at the baseline visit. Associations between CKD prevalence and awareness and selected demographic, socioeconomic, healthcare access, and disease status parameters were assessed utilizing logistic regression models.

Results

The prevalence of CKD in the JHS was 20%; CKD awareness was only 15.8%. Older participants had higher prevalence but were also more aware of CKD. Hypertension, diabetes, cardiovascular disease (CVD), hypercholesterolemia, hypertriglyceridemia, increasing age and waist circumference as well as being single or less physically active were associated with CKD. Only advancing of CKD stage was associated with awareness.

Limitations

Cross-sectional assessment, single urine measurement

Conclusions

The JHS has a high prevalence and low awareness of CKD, especially those with less severe disease status. This emphasizes the need for earlier diagnosis and increased education of health care providers and the general population.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.

Author Summary

Many African Americans have white blood cell counts (WBC) that are persistently below the normal range for people of European descent, a condition called “benign ethnic neutropenia.” Because most African Americans have both African and European ancestors, selected genetic variants can be analyzed to assign probable African or European origin to each region of each such person's chromosomes. Previously, we found a region on chromosome 1 where increased local African ancestry completely accounted for differences in WBC between African and European Americans, suggesting the presence of an African-derived variant causing low WBC. Here, we show that low neutrophil count is predominantly responsible for low WBC; that a dominant, European-derived allele contributes to high neutrophil count; and that the frequency of this allele differs in Africans and Europeans by >91%. Across the chromosome 1 locus, only the well-characterized “Duffy” polymorphism was this differentiated. Neutrophil count was more strongly associated to the Duffy variant than to ancestry, suggesting that the variant itself causes benign ethnic neutropenia. The African, or “null,” form of this variant abolishes expression of the “Duffy Antigen Receptor for Chemokines” on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration.

Background

African Americans have historically had high HDL-C compared to other races and ethnicities.

Objective

We sought to characterize whether there is a cross-sectional association between age and HDL-C in a contemporary community-based study of African Americans.

Methods

Cross-sectional data was modeled by logistic regression for predictors of HDL-C among African-Americans, ages 35–74, participating in the baseline examination of a community-based study of cardiovascular disease in Jackson, MS, during 2000–2004. After excluding persons taking lipid-lowering medications, hormone replacement therapy, oral contraceptives, or thyroid replacement, the analytical data set comprised 2420 persons (1370 women, 1050 men).

Results

HDL-C had a significant positive association with age after controlling for serum triglycerides, sex, waist circumference, percent dietary calories from carbohydrates, alcohol use, and leisure physical activity. Sex was a significant effect modifier of this relationship, whereby the increase in HDL-C with age was steeper for women than for men.

Conclusions

Cross-sectional analysis found a positive association of HDL-C with age while controlling for triglycerides. Careful evaluation of longitudinal data will be needed to confirm whether this is a true effect of aging, or a cohort or survivor effect.

Background

Socioeconomic status (SES) is recognized as a key social environmental factor because it has implications for access to resources that help individuals care for themselves and others. Few studies have examined the association of SES with CKD in high-risk populations.

Study Design

Single-site longitudinal population-based cohort

Setting and Participants

The data for this study were drawn from the baseline examination of the Jackson Heart Study. The analytic cohort consisted of 3,430 African American men and women living in the tri-county area of the Jackson, Mississippi metropolitan areas with complete data to determine CKD status.

Predictor

High SES (defined as having a family income at least 3.5 times the poverty level or having at least one undergraduate degree)

Outcomes and Measurements

CKD (defined as the presence of albuminuria or reduced estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2). Associations were explored through bivariable analyses and multivariable logistic regression analyses adjusting for CKD and cardiovascular disease risk factors as well as demographic factors.

Results

The prevalence of CKD in the Jackson Heart Study was 20% (865/3430 participants). The proportion of the Jackson Heart Study cohort with albuminuria and decreased eGFR was 12.5% (429/3430 participants) and 10.1% (347/3430 participants) respectively. High SES was inversely associated with CKD. The odds of having CKD were 41% lower for affluent participants than their less affluent counterparts. There were no statistically significant interactions between sex and education or income although subgroup analysis showed that high income was associated with CKD among male (OR 0.47, CI 0.23–0.97) but not female (OR 0.64, CI 0.40–1.03) participants.

Limitations

Models were estimated using cross-sectional data.

Conclusion

CKD is associated with SES. Additional research is needed to elucidate the impact of wealth and social contexts in which individuals are embedded, and the mediating effects of sociocultural factors.

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

Author Summary

This paper presents improved methodologies for the analysis of genome-wide association studies in admixed populations, which are populations that came about by the mixing of two or more distant continental populations over a few hundred years (e.g., African Americans or Latinos). Studies of admixed populations offer the promise of capturing additional genetic diversity compared to studies over homogeneous populations such as Europeans. In admixed populations, correlation between genetic variants exists both at a fine scale in the ancestral populations and at a coarse scale due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered either one or the other type of correlation, but not both. In this work we develop novel statistical methods that account for both types of genetic correlation, and we show that the combined approach attains greater statistical power than that achieved by applying either approach separately. We provide analysis of simulated and real data from major studies performed in African-American men and women to show the improvement obtained by our methods over the standard methods for analyzing association studies in admixed populations.

Background

African Americans have an increased incidence and worse prognosis with chronic kidney disease (CKD - estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) than their counterparts of European-descent. Inflammation has been related to renal disease in non-Hispanic whites, but there are limited data on the role of inflammation in renal dysfunction in African Americans in the community.

Methods

We examined the cross-sectional relation of log transformed C-reactive protein (CRP) to renal function (eGFR by Modification of Diet and Renal Disease equation) in African American participants of the community-based Jackson Heart Study's first examination (2000 to 2004). We conducted multivariable linear regression relating CRP to eGFR adjusting for age, sex, body mass index, systolic and diastolic blood pressure, diabetes, total/HDL cholesterol, triglycerides, smoking, antihypertensive therapy, lipid lowering therapy, hormone replacement therapy, and prevalent cardiovascular disease events. In a secondary analysis we assessed the association of CRP with albuminuria (defined as albumin-to-creatinine ratio > 30 mg/g).

Results

Participants (n = 4320, 63.2% women) had a mean age ± SD of 54.0 ± 12.8 years. The prevalence of CKD was 5.2% (n = 228 cases). In multivariable regression, CRP concentrations were higher in those with CKD compared to those without CKD (mean CRP 3.2 ± 1.1 mg/L vs. 2.4 ± 1.0 mg/L, respectively p < 0.0001). CRP was significantly associated with albuminuria in sex and age adjusted model however not in the multivariable adjusted model (p > 0.05).

Conclusion

CRP was associated with CKD however not albuminuria in multivariable-adjusted analyses. The study of inflammation in the progression of renal disease in African Americans merits further investigation.

The prevalence of obesity (body mass index (BMI) ≥30 kg/m2) 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 (ρ = −0.042, P = 1.6×10−7). 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.

Author Summary

Obesity is about 1.5-fold more prevalent in African Americans than European Americans. To determine whether genetic background may contribute to this observed disparity, we scanned the genomes of African Americans, searching for genomic regions where obese individuals have a difference from the average proportion of African ancestry. By examining genetic data from more than 15,000 African Americans, we show that the proportion of European ancestry is inversely correlated with BMI. In obese individuals, we detect two loci with increased African ancestry on chromosome X (Xq13.1 and Xq25) and one locus with increased European ancestry on chromosome 5 (5q13.3). The 5q13.3 and Xq25 regions both contain genes that are known to be involved in appetite regulation. Our results suggest that genetic factors may contribute to the difference in obesity prevalence between African Americans and European Americans. Further studies of the regions may identify the causative variants affecting susceptibility to obesity.