RESUMO
We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.
Assuntos
Negro ou Afro-Americano , Hispânico ou Latino , Americanos Mexicanos , Humanos , Negro ou Afro-Americano/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Americanos Mexicanos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , TranscriptomaRESUMO
Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.
Assuntos
Variação Genética , Indígenas Norte-Americanos/genética , Americanos Mexicanos/genética , População/genética , População Negra/genética , Genoma Humano , Humanos , México , População Branca/genéticaRESUMO
MOTIVATION: It is becoming increasingly evident that the analysis of genotype data from recently admixed populations is providing important insights into medical genetics and population history. Such analyses have been used to identify novel disease loci, to understand recombination rate variation and to detect recent selection events. The utility of such studies crucially depends on accurate and unbiased estimation of the ancestry at every genomic locus in recently admixed populations. Although various methods have been proposed and shown to be extremely accurate in two-way admixtures (e.g. African Americans), only a few approaches have been proposed and thoroughly benchmarked on multi-way admixtures (e.g. Latino populations of the Americas). RESULTS: To address these challenges we introduce here methods for local ancestry inference which leverage the structure of linkage disequilibrium in the ancestral population (LAMP-LD), and incorporate the constraint of Mendelian segregation when inferring local ancestry in nuclear family trios (LAMP-HAP). Our algorithms uniquely combine hidden Markov models (HMMs) of haplotype diversity within a novel window-based framework to achieve superior accuracy as compared with published methods. Further, unlike previous methods, the structure of our HMM does not depend on the number of reference haplotypes but on a fixed constant, and it is thereby capable of utilizing large datasets while remaining highly efficient and robust to over-fitting. Through simulations and analysis of real data from 489 nuclear trio families from the mainland US, Puerto Rico and Mexico, we demonstrate that our methods achieve superior accuracy compared with published methods for local ancestry inference in Latinos.
Assuntos
Algoritmos , Genética Populacional , Hispânico ou Latino/genética , Fluxo Gênico , Genética Populacional/métodos , Haplótipos , Humanos , Indígenas Norte-Americanos/genética , Desequilíbrio de Ligação , Cadeias de Markov , México , Porto Rico , Estados Unidos , População Branca/genéticaRESUMO
The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63-68%), 31% Indigenous American (28-33%) and 4% African (3-4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73-79%; Northeast (NEA) 54%, 95%CI: 49-58%; Northwest (NWA) 33%, 95%CI: 21-41%; South 54%, 95%CI: 49-59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75-86%) versus 68% (95%CI: 58-77%), pâ=â0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88-94%) compared to 54% (95%CI: 51-57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population.
Assuntos
Etnicidade/genética , Variação Genética , Grupos Raciais/genética , Argentina , Mapeamento Cromossômico/métodos , Feminino , Genética Populacional/métodos , Genótipo , Humanos , MasculinoRESUMO
BACKGROUND: The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent. OBJECTIVE: To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children. PATIENTS AND METHODS: There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression. RESULTS: Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year. CONCLUSIONS: Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.
Assuntos
Asma/etnologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/epidemiologia , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Asma/epidemiologia , Criança , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Modelos Logísticos , Bem-Estar Materno , Americanos Mexicanos/estatística & dados numéricos , Gravidez , Porto Rico/etnologiaRESUMO
Contemporary genetic variation among Latin Americans human groups reflects population migrations shaped by complex historical, social and economic factors. Consequently, admixture patterns may vary by geographic regions ranging from countries to neighborhoods. We examined the geographic variation of admixture across the island of Puerto Rico and the degree to which it could be explained by historic and social events. We analyzed a census-based sample of 642 Puerto Rican individuals that were genotyped for 93 ancestry informative markers (AIMs) to estimate African, European and Native American ancestry. Socioeconomic status (SES) data and geographic location were obtained for each individual. There was significant geographic variation of ancestry across the island. In particular, African ancestry demonstrated a decreasing East to West gradient that was partially explained by historical factors linked to the colonial sugar plantation system. SES also demonstrated a parallel decreasing cline from East to West. However, at a local level, SES and African ancestry were negatively correlated. European ancestry was strongly negatively correlated with African ancestry and therefore showed patterns complementary to African ancestry. By contrast, Native American ancestry showed little variation across the island and across individuals and appears to have played little social role historically. The observed geographic distributions of SES and genetic variation relate to historical social events and mating patterns, and have substantial implications for the design of studies in the recently admixed Puerto Rican population. More generally, our results demonstrate the importance of incorporating social and geographic data with genetics when studying contemporary admixed populations.
Assuntos
Genética Populacional , Genoma Humano/genética , Grupos Raciais/genética , Geografia , Humanos , Porto Rico/etnologia , Comportamento SocialRESUMO
BACKGROUND: Ethnic-specific interactions between different asthma medications are not well described. OBJECTIVE: To determine whether the use of leukotriene modifiers is associated with the magnitude of bronchodilator responsiveness among Mexican American and Puerto Rican children with persistent asthma. METHODS: A cross-sectional study of 84 Mexican American and 192 Puerto Rican children, with persistent asthma who were aged 8 to 16 years. Within each group, bronchodilator responsiveness to albuterol, objectively assessed via spirometry, was compared between participants using leukotriene modifiers and those not using leukotriene modifiers. RESULTS: Leukotriene modifier use was associated with a clinically significant increase in percentage change in forced expiratory volume in 1 second of 11.8 (P < .001) in Puerto Rican children, but there was no significant change in percentage change in forced expiratory volume in 1 second (-3.2, P=.57) in Mexican American children. This finding persisted after controlling for the use of inhaled corticosteroids. In addition, among the Puerto Rican children, the association between leukotriene modifier use and augmented bronchodilator responsiveness was greatest in those younger than 12 years. CONCLUSIONS: Among children with persistent asthma, use of leukotriene modifiers is associated with augmented bronchodilator responsiveness to albuterol in Puerto Ricans, but not Mexican Americans. This ethnic-specific, drug-drug interaction highlights the need for the further understanding of asthma pharmacogenetics among children from different ethnic groups to improve asthma outcomes.
Assuntos
Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Interações Medicamentosas , Antagonistas de Leucotrienos/administração & dosagem , Adolescente , Albuterol/administração & dosagem , Asma/etnologia , Criança , Estudos Transversais , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Hispânico ou Latino , Humanos , Masculino , Americanos Mexicanos , Resultado do TratamentoRESUMO
OBJECTIVE: A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients. METHODS: Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses. RESULTS: No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol. CONCLUSION: Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.
Assuntos
Asma/tratamento farmacológico , Asma/genética , Broncodilatadores/uso terapêutico , Farmacogenética , Filogenia , Adolescente , Adulto , Negro ou Afro-Americano/genética , Indígena Americano ou Nativo do Alasca/genética , Estudos de Casos e Controles , Criança , Demografia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Interleucina-6/genética , Modelos Lineares , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Porto Rico/etnologia , Receptores de Interleucina-6/genéticaRESUMO
OBJECTIVES: We investigated the Latino paradox in a managed care setting and examined the role of birthplace. METHODS: We evaluated 133,155 non-Latino Whites and 5,237 Latinos (36% born in the United States, 34% in Central and South America, 21% in Mexico, and 8% in the Caribbean Islands) who were enrolled in an integrated healthcare delivery system in northern California. Baseline data were from 1964-1973, and the median followup was 34 years. Main outcome measures were cause-specific and all-cause mortality. RESULTS: In fully-adjusted analyses, and compared with non-Latino Whites, the risk of death from circulatory causes was significantly lower among US-born Latinos (hazard ratio [HR] .79, 95% confidence interval [CI] .66-.93), among Central and South America-born Latinos (HR .76, 95% CI .63-.91), and Caribbean-born Latinos (HR .66, 95% CI .47-0.93). Risk of death by malignant neoplasms was significantly lower among US-born Latinos (HR .68, 95% CI .56-.83). Risk of respiratory death was significantly lower among Central and South America-born Latinos (HR .50, 95% CI .32-.80). All-cause mortality risk was significantly decreased in US-born Latinos (HR .79, 95% CI .71-.87), Central and South America-born Latinos (HR .81, 95% CI .73-.90), and Caribbean-born Latinos (HR .76, 95% CI .63-.93) but not in Mexico-born Latinos. CONCLUSIONS: In our managed care setting, the Latino paradox phenomenon varied by birthplace; it was more evident among US-born Latinos. This subgroup experienced lower circulatory, cancer, and all-cause mortality than did non-Latino Whites, despite higher prevalences of current smoking, obesity, and asymptomatic hyperglycemia.
Assuntos
Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/mortalidade , Prestação Integrada de Cuidados de Saúde , Disparidades nos Níveis de Saúde , Hispânico ou Latino/estatística & dados numéricos , População Branca/estatística & dados numéricos , Adulto , California , América Central/etnologia , Estudos de Coortes , Feminino , Humanos , Masculino , México/etnologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , América do Sul/etnologia , Índias Ocidentais/etnologiaRESUMO
While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population, which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico's founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico's founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation.