Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11–34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10^-15] in African populations, rs11549407 with lower HGB [p = 1.5x10^-12] and HCT [p = 8.8x10^-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations. Admixed African and Hispanic/Latino populations remain understudied in genetic studies of complex diseases. These populations have more complex linkage disequilibrium (LD) structure that can impair mapping of variants. Genotype imputation represents an approach to improve genome coverage, especially for rare or ancestry-specific variation; however, these understudied populations also have smaller relevant imputation reference panels. In this study, we leveraged >100,000 phased sequences generated from the multi-ethnic NHLBI TOPMed project for imputation in ~21,600 individuals of African ancestry (AAs) and ~21,700 Hispanics/Latinos. We demonstrated substantially higher imputation quality for low frequency and rare variants in comparison to the 1000 Genomes Project and Haplotype Reference Consortium reference panels. Analysis of quantitative hematological traits led to the discovery of associations with two rare variants in the HBB gene; one of these variants was replicated in an independent sample, and the other is known to cause anemia in the homozygous state. By comparison, the same HBB variants would not have been genome-wide significant using current reference panels due to lower imputation quality. Our findings demonstrate the power of TOPMed whole genome sequencing data for imputation and subsequent association analysis in admixed African and Hispanic/Latino populations.

Rice accumulates 10-fold higher inorganic arsenic (i-As), an established human carcinogen, than other grains. This review summarizes epidemiologic studies that examined the association between rice consumption and biomarkers of arsenic exposure. After reviewing the literature we identified 20 studies, among them included 18 observational and 2 human experimental studies that reported on associations between rice consumption and an arsenic biomarker. Among individuals not exposed to contaminated water, rice is a source of i-As exposure - rice consumption has been consistently related to arsenic biomarkers, and the relationship has been clearly demonstrated in experimental studies. Early-life i-As exposure is of particular concern due to its association with lifelong adverse health outcomes. Maternal rice consumption during pregnancy also has been associated with infant toenail total arsenic concentrations indicating that dietary exposure during pregnancy results in fetal exposure. Thus, the collective evidence indicates that rice is an independent source of arsenic exposure in populations around the world and highlights the importance of investigating its affect on health.

Exposure to cadmium, cobalt, lead, and manganese has been associated with decreased pulmonary function in adults. Little is known about the magnitude of these associations among children in the United States. We evaluated cross-sectional associations of blood and urinary concentrations of cadmium, cobalt, lead, and manganese with pulmonary function measures [forced expiratory volume in one second (FEV1; milliliters), forced vital capacity (FVC; milliliters), ratio of FEV1 to FVC (FEV1:FVC), and mid-exhalation forced expiratory flow rate (FEF 25-75%; milliliters/second)] in a sample of 1234 6-17 year olds, who participated in the 2011-2012 survey cycle of the National Health and Nutrition Examination Survey (NHANES). Survey-weighted linear regression was used to estimate beta coefficients and 95% confidence intervals (CIs) for the associations between metal exposure tertiles or quartiles and pulmonary function test parameters, with adjustment for relevant covariates. Blood manganese concentration was inversely associated with FVC (β for highest versus lowest quartile = -97.1, 95% CI = -230.6, 36.4; p for trend = 0.03). Urinary manganese was inversely associated with FEV1:FVC and FEF 25-75% (p for trend = 0.05 and 0.02, respectively). Urinary lead was inversely associated with FEF 25-75% (p for trend = 0.01). The associations between blood manganese and both FEV1 and FVC differed by age (p for interaction = 0.04 and 0.04, respectively), indicating an inverse trend that was strongest among older youth. Environmental exposure to manganese and lead may adversely impact the pulmonary function of young people in the United States. Our findings highlight a need to prioritize children's environmental health and evaluate these associations prospectively.

A peer-reviewed open access journal published by the National Institute of Environmental Health Sciences