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BackgroundCirculating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented.ResultsWe performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations.ConclusionsOur results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p

RationaleAdverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking.ObjectivesTo assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry.MethodsThe study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 μm and ≤2.5 μm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry.Measurements and main resultsA 5 μg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 μm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function.ConclusionsEarly-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.

BackgroundIgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders.ObjectiveWe sought to identify genetic variants associated with IgE levels in Latinos.MethodsWe performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies.ResultsWe confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011).ConclusionWe confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels.

BackgroundChildhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest.ObjectiveTo determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children.MethodsWe analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry.ResultsNative American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively).ConclusionDifferences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.

It has long been accepted that modern reproductive patterns are likely contributors to breast cancer susceptibility because of their influence on hormones such as estrogen and the importance of these hormones in breast cancer. We conducted a meta-analysis to assess whether this 'evolutionary mismatch hypothesis' can explain susceptibility to both estrogen receptor positive (ER-positive) and estrogen receptor negative (ER-negative) cancer. Our meta-analysis includes a total of 33 studies and examines parity, age of first birth and age of menarche broken down by estrogen receptor status. We found that modern reproductive patterns are more closely linked to ER-positive than ER-negative breast cancer. Thus, the evolutionary mismatch hypothesis for breast cancer can account for ER-positive breast cancer susceptibility but not ER-negative breast cancer.

It has long been accepted that modern reproductive patterns are likely contributors to breast cancer susceptibility because of their influence on hormones such as estrogen and the importance of these hormones in breast cancer. We conducted a meta-analysis to assess whether this 'evolutionary mismatch hypothesis' can explain susceptibility to both estrogen receptor positive (ER-positive) and estrogen receptor negative (ER-negative) cancer. Our meta-analysis includes a total of 33 studies and examines parity, age of first birth and age of menarche broken down by estrogen receptor status. We found that modern reproductive patterns are more closely linked to ER-positive than ER-negative breast cancer. Thus, the evolutionary mismatch hypothesis for breast cancer can account for ER-positive breast cancer susceptibility but not ER-negative breast cancer.

RationaleAir pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications.ObjectivesTo assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions.MethodsThis study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO₂), sulfur dioxide, particulate matter not greater than 10 μm in diameter, and particulate matter not greater than 2.5 μm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant.Measurements and main resultsAfter adjustment for confounders, a 5-ppb increase in average NO₂ during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04-1.31).ConclusionsEarly-life NO₂ exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine. Author summary: Blood lipid levels are closely linked to cardio-metabolic diseases, and genetic factors play an important role in their metabolism and regulation. Although over 400 loci have been identified through genetic association studies, the genetic architecture of lipid levels is not fully characterized. The lack of representation of diverse populations in previous studies resulted in a large gap in understanding the genetic background of lipid traits between European and minority populations, including African Americans, Hispanics, Hawaiians, and Native Americans. In our current analyses which included ancestrally diverse populations, we identified nine novel loci, one novel gene, and minority-specific independent signals at eight known loci, and pinpointed potential functional variants at two known loci. We further observed smaller effect sizes of reported lipids-associated loci in African Americans and Hispanics than those in Europeans, and better performance of polygenic risk scores using minority-specific instead of European-derived effect sizes when estimating genetic predisposition in minority populations. Our findings showed the benefits of including multi-ethnic studies in identification and refinement of lipids-associated loci, which will help to reduce the existing disparities and to pave the road to precision medicine. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory infections are a major cause of morbidity in children and are often caused by viruses. However, the relative severity of illness associated with different viruses is unclear. The objective of this study was to evaluate the risk of hospitalization from different viruses in children presenting with an influenza‐like illness (ILI). Methods: Data from children 5 years old or younger participating in an ILI natural history study from April 2010 to March 2014 was analyzed. The adjusted odds ratio for hospitalization was estimated in children with infections caused by respiratory syncytial virus (RSV), metapneumovirus, bocavirus, parainfluenza viruses, rhinovirus/enterovirus, coronavirus, adenovirus, and influenza. Results: A total of 1486 children (408 outpatients and 1078 inpatients) were included in this analysis. At least one virus was detected in 1227 (82.6%) patients. The most frequent viruses detected as single pathogens were RSV (n = 286), rhinovirus/enterovirus (n = 251), parainfluenza viruses (n = 104), and influenza A or B (n = 99). After controlling for potential confounders (age, sex, recruitment site, days from symptom onset to enrollment, and underlying illnesses), children with RSV and metapneumovirus infections showed a greater likelihood of hospitalization than those infected by parainfluenza viruses (OR 2.7 and 1.9, respectively), rhinovirus/enterovirus (OR 3.1 and 2.1, respectively), coronaviruses (OR 4.9 and 3.4, respectively), adenovirus (OR 4.6 and 3.2, respectively), and influenza (OR 6.3 and 4.4, respectively). Conclusions: Children presenting with ILI caused by RSV and metapneumovirus were at greatest risk for hospitalization, while children with rhinovirus/enterovirus, parainfluenza, coronavirus, adenovirus, and influenza were at lower risk of hospitalization. [ABSTRACT FROM AUTHOR]

Introduction: Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index commonly used in clinical workup of anemia. Macrocytosis, or high MCV, is associated with cardiovascular events in chronic kidney disease patients and all-cause mortality. Genome-wide association studies (GWAS) of MCV have been conducted primarily in European and Asian populations; few have included populations of African or American ancestry. The Multiethnic Genotyping Array (MEGA) was designed to improve variant discovery and fine-mapping in US minorities by better capturing population-specific genetic variation. To identify novel MCV loci and examine evidence of generalization of previously reported MCV loci to populations with African and Amerindian genetic admixture, we conducted a GWAS of African American and Hispanic/Latino Population Architecture using Genomics and Epidemiology (PAGE II) participants on the MEGA array. Methods: We employed Illumina MEGA genotype data to evaluate the association between ~1.5 million SNPs and MCV. Generalized estimating equation models were adjusted for age, sex, current smoking status, study, study center, and the top 10 study-specific principal components of genetic ancestry. Race/ethnic-stratified analyses were combined using inverse-variance weighted fixed-effects meta-analysis to evaluate the entire study sample. Significance thresholds of 1.8x10-3 and 5x10-8 were used to define generalization and genome-wide significance, respectively. Results: The study population of 3,734 African Americans and 15,505 Hispanic/Latinos was 62% female with a mean age of 50 (range: 18 to 94 years); 19% of participants were current smokers. Trans-ethnic meta-analysis identified 12 genome-wide significant loci for MCV, including two associations at previously unreported loci: FIGNL1/IKZF1 (chromosome 7p12.2, coded allele frequency [CAF] range=51 to 57%), and LRP6 (chromosome 12p13.2, CAF range=0.3 to 1.7%). FIGNL1 is involved in DNA double-strand-break repair, and IKZF1 is a zinc-finger protein that functions in the hemo-lymphopoetic system. LRP6 encodes an LDL receptor involved in the Wnt/beta-catenin signaling cascade. Ninety-three percent of previously reported MCV loci generalized to the combined PAGE study population, ten at genome-wide significant levels. No previously unreported MCV loci were detected in race/ethnic stratified analyses. Conclusion: Generalization of previously reported MCV loci to African Americans and Hispanic/Latinos highlights the shared genetic architecture of MCV. The potentially novel associations identified at chromosomes 7p12.2 and 12p13.2 also underscore the benefits of performing GWAS in ancestrally diverse populations using arrays that better capture global genetic variation. [ABSTRACT FROM AUTHOR]