Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of ...Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10−28) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits.
Abstract Causal gene discovery methods are often evaluated using reference sets of causal genes, which are treated as gold standards (GS) for the purposes of evaluation. However, evaluation methods ...typically treat genes not in the GS positive set as known negatives rather than unknowns. This leads to inaccurate estimates of sensitivity, specificity, and AUC. Labeling biases in GS gene sets can also lead to inaccurate ordering of alternative causal gene discovery methods. We argue that the evaluation of causal gene discovery methods should rely on statistical techniques like those used for variant discovery rather than on comparison with GS gene sets.
It has been shown that EPA Method 3060A does not adequately extract Cr(VI) from chromium ore processing residue (COPR). We modified various parameters of EPA 3060A toward understanding the ...transformation of COPR minerals in the alkaline extraction and improving extraction of Cr(VI) from NIST SRM 2701, a standard COPR-contaminated soil. Aluminum and Si were the major elements dissolved from NIST 2701, and their concentrations in solution were correlated with Cr(VI). The extraction fluid leached additional Al and Si from the method-prescribed borosilicate glass vessels which appeared to suppress the release of Cr(VI). Use of polytetrafluoroethylene vessels and intensive grinding of NIST 2701 increased the amount of Cr(VI) extracted. These modifications, combined with an increased extraction fluid to sample ratio of ≥900 mL g–1 and 48-h extraction time resulted in a maximum release of 1274 ± 7 mg kg–1 Cr(VI). This is greater than the NIST 2701 certified value of 551 ± 35 mg kg–1 but less than 3050 mg kg–1 Cr(VI) previously estimated by X-ray absorption near edge structure spectroscopy. Some of the increased Cr(VI) may have resulted from oxidation of Cr(III) released from brownmillerite which rapidly transformed during the extractions. Layered-double hydroxides remained stable during extractions and represent a potential residence for unextracted Cr(VI).
► Southern Sacramento Valley soil and sediment has abundant naturally-occurring Cr(III). ► Cr(III) resides mainly in chromite but some is associated with clays and Fe oxides. ► Cr(VI) is mostly ...absent in surface soil but ubiquitous in deeper soil and sediment. ► Cr(VI) increased linearly with time during lab soil incubations with no additions. ► Cation exchange processes resulted in greater Cr(VI) generation rates.
Concentrations of geogenic Cr(VI) in groundwater that exceed the World Health Organization’s maximum contaminant level for drinking water (50
μg
L
−1) occur in several locations globally. The major mechanism for mobilization of this Cr(VI) at these sites is the weathering of Cr(III) from ultramafic rocks and its subsequent oxidation on Mn oxides. This process may be occurring in the southern Sacramento Valley of California where Cr(VI) concentrations in groundwater can approach or exceed 50
μg
L
−1. To characterize Cr geochemistry in the area, samples from several soil auger cores (approximately 4
m deep) and drill cores (approximately 25
m deep) were analyzed for total concentrations of 44 major, minor and trace elements, Cr associated with labile Mn and Fe oxides, and Cr(VI). Total concentrations of Cr in these samples ranged from 140 to 2220
mg per kg soil. Between 9 and 70
mg per kg soil was released by selective extractions that target Fe oxides, but essentially no Cr was associated with the abundant reactive Mn oxides (up to ∼1000
mg hydroxylamine-reducible Mn per kg soil was present). Both borehole magnetic susceptibility surveys performed at some of the drill core sites and relative differences between Cr released in a 4-acid digestion versus total Cr (lithium metaborate fusion digestion) suggest that the majority of total Cr in the samples is present in refractory chromite minerals transported from ultramafic exposures in the Coast Range Mountains. Chromium(VI) in the samples studied ranged from 0 to 42
μg
kg
−1, representing a minute fraction of total Cr. Chromium(VI) content was typically below detection in surface soils (top 10
cm) where soil organic matter was high, and increased with increasing depth in the soil auger cores as organic matter decreased. Maximum concentrations of Cr(VI) were up to 3 times greater in the deeper drill core samples than the shallow auger cores. Although Cr(VI) in these vadose zone soils and sediments was only a very small fraction of the total solid phase Cr, they are a potentially important source for Cr(VI) to groundwater. Enhanced groundwater recharge through the vadose zone due to irrigation could carry Cr(VI) from the vadose zone to the groundwater and may be the mechanism responsible for the correlation observed between elevated Cr(VI) and
NO
3
-
concentrations in previously published data for valley groundwaters. Incubation of a valley subsoil showed a Cr(VI) production rate of 24
μg
kg
−1
a
−1 suggesting that field Cr(VI) concentrations could be regenerated annually. Increased Cr(VI) production rates in H
+-amended soil incubations indicate that soil acidification processes such as nitrification of ammonium in fertilizers could potentially increase the occurrence of geogenic Cr(VI) in groundwater. Thus, despite the natural origin of the Cr, Cr(VI) generation in the Sacramento Valley soils and sediments has the potential to be influenced by human activities.
This study addresses the geologic and hydrogeochemical processes operating at a range of scales within the prairie pothole region (PPR). The PPR is a 750,000km2 portion of north central North America ...that hosts millions of small wetlands known to be critical habitat for waterfowl and other wildlife. At a local scale, we characterized the geochemical evolution of the 92-ha Cottonwood Lake study area (CWLSA), located in North Dakota, USA. Critical zone processes are the long-term determinant of wetland water and groundwater geochemistry via the interaction of oxygenated groundwater with pyrite in the underlying glacial till. Pyrite oxidation produced a brown, iron oxide-bearing surface layer locally over 13m thick and an estimated minimum of 1.3×1010g sulfate (SO42−) at CWLSA. We show that the majority of this SO42− now resides in solid-phase gypsum (CaSO4•2H2O) and gypsum-saturated groundwater.
Results from the CWLSA were scaled up to a 9700km2 area surrounding CWLSA using ~1800 drill logs and literature data on wetland water chemistry for 178 wetlands within this larger area. The oxidized brown zone depth and wetland water compositional trends are very similar to the CWLSA. Additionally, surface water data from 176 southern Canadian pothole wetlands that conform to the same wetland water geochemical trends as those recorded in the CWLSA further corroborate that SO42− accumulation driven by pyrite oxidation is a nearly ubiquitous process in the prairie pothole region and distinguishes PPR wetlands from other wetlands worldwide that have a similar overall hydrology.
•We quantified alteration of glacial till in the prairie pothole region of the US.•Alteration was characterized at multiple scales using drill-hole and water data.•Pyrite oxidation and carbonate dissolution in till determine groundwater chemistry.•Internal wetland geochemical processes transform groundwater to wetland water.•Similar processes operate throughout the prairie pothole region.
Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ...ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.
Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in ...cohorts of European ancestry.
Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations.
GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies.
Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV
in ZSWIM7 (rs4791658; P = 4.99 × 10
) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV
/FVC (P = 9.59 × 10
) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV
, which replicated. A novel locus for FEV
identified among ever smokers (rs291231; P = 1.92 × 10
) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 × 10
) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome-wide significance level.
We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.
Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring ...of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, basophils) differ by ethnicity. The genetic factors underlying basal WBC traits in Hispanics/Latinos are ...unknown. We performed a genome-wide association study of total WBC and differential counts in a large, ethnically diverse US population sample of Hispanics/Latinos ascertained by the Hispanic Community Health Study and Study of Latinos (HCHS/SOL). We demonstrate that several previously known WBC-associated genetic loci (e.g. the African Duffy antigen receptor for chemokines null variant for neutrophil count) are generalizable to WBC traits in Hispanics/Latinos. We identified and replicated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) associated with monocyte count. The common FLT3 variant rs76428106 has a large allele frequency differential between African and non-African populations. We also identified several novel genetic loci involving or regulating hematopoietic transcription factors (CEBPE-SLC7A7, CEBPA and CRBN-TRNT1) associated with basophil count. The minor allele of the CEBPE variant associated with lower basophil count has been previously associated with Amerindian ancestry and higher risk of acute lymphoblastic leukemia in Hispanics. Together, these data suggest that germline genetic variation affecting transcriptional and signaling pathways that underlie WBC development and lineage specification can contribute to inter-individual as well as ethnic differences in peripheral blood cell counts (normal hematopoiesis) in addition to susceptibility to leukemia (malignant hematopoiesis).
Dental caries is the most common chronic disease worldwide, and exhibits profound disparities in the USA with racial and ethnic minorities experiencing disproportionate disease burden. Though ...heritable, the specific genes influencing risk of dental caries remain largely unknown. Therefore, we performed genome-wide association scans (GWASs) for dental caries in a population-based cohort of 12 000 Hispanic/Latino participants aged 18-74 years from the HCHS/SOL. Intra-oral examinations were used to generate two common indices of dental caries experience which were tested for association with 27.7 M genotyped or imputed single-nucleotide polymorphisms separately in the six ancestry groups. A mixed-models approach was used, which adjusted for age, sex, recruitment site, five principal components of ancestry and additional features of the sampling design. Meta-analyses were used to combine GWAS results across ancestry groups. Heritability estimates ranged from 20-53% in the six ancestry groups. The most significant association observed via meta-analysis for both phenotypes was in the region of the NAMPT gene (rs190395159; P-value = 6 × 10(-10)), which is involved in many biological processes including periodontal healing. Another significant association was observed for rs72626594 (P-value = 3 × 10(-8)) downstream of BMP7, a tooth development gene. Other associations were observed in genes lacking known or plausible roles in dental caries. In conclusion, this was the largest GWAS of dental caries, to date and was the first to target Hispanic/Latino populations. Understanding the factors influencing dental caries susceptibility may lead to improvements in prediction, prevention and disease management, which may ultimately reduce the disparities in oral health across racial, ethnic and socioeconomic strata.
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