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1.
Nature ; 583(7814): 83-89, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460305

RESUMO

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.


Assuntos
Variação Genética , Genoma Humano/genética , Sequenciamento Completo do Genoma , Alelos , Estudos de Casos e Controles , Grupos de Populações Continentais/genética , Epigênese Genética , Feminino , Dosagem de Genes/genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Anotação de Sequência Molecular , Locos de Características Quantitativas , Software
2.
Nat Commun ; 11(1): 1674, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245946

RESUMO

Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.


Assuntos
Proteínas CELF1/metabolismo , Proteína Semelhante a ELAV 4/genética , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/crescimento & desenvolvimento , Neurogênese/genética , Regiões 5' não Traduzidas/genética , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neocórtex/citologia , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Polirribossomos/metabolismo , Cultura Primária de Células , Biossíntese de Proteínas/genética , Isoformas de RNA/genética , RNA-Seq
3.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226016

RESUMO

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.


Assuntos
Grupos de Populações Continentais/genética , Lipídeos/sangue , Lipídeos/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lipídeos/análise , Masculino , Metagenômica/métodos , Grupos Minoritários , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
4.
Genes (Basel) ; 10(9)2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546899

RESUMO

Informatics researchers often need to combine data from many different sources to increase statistical power and study subtle or complicated effects. Perfect overlap of measurements across academic studies is rare since virtually every dataset is collected for a unique purpose and without coordination across parties not-at-hand (i.e., informatics researchers in the future). Thus, incomplete concordance of measurements across datasets poses a major challenge for researchers seeking to combine public databases. In any given field, some measurements are fairly standard, but every organization collecting data makes unique decisions on instruments, protocols, and methods of processing the data. This typically denies literal concatenation of the raw data since constituent cohorts do not have the same measurements (i.e., columns of data). When measurements across datasets are similar prima facie, there is a desire to combine the data to increase power, but mixing non-identical measurements could greatly reduce the sensitivity of the downstream analysis. Here, we discuss a statistical method that is applicable when certain patterns of missing data are found; namely, it is possible to combine datasets that measure the same underlying constructs (or latent traits) when there is only partial overlap of measurements across the constituent datasets. Our method, ROSETTA empirically derives a set of common latent trait metrics for each related measurement domain using a novel variation of factor analysis to ensure equivalence across the constituent datasets. The advantage of combining datasets this way is the simplicity, statistical power, and modeling flexibility of a single joint analysis of all the data. Three simulation studies show the performance of ROSETTA on datasets with only partially overlapping measurements (i.e., systematically missing information), benchmarked to a condition of perfectly overlapped data (i.e., full information). The first study examined a range of correlations, while the second study was modeled after the observed correlations in a well-characterized clinical, behavioral cohort. Both studies consistently show significant correlations >0.94, often >0.96, indicating the robustness of the method and validating the general approach. The third study varied within and between domain correlations and compared ROSETTA to multiple imputation and meta-analysis as two commonly used methods that ostensibly solve the same data integration problem. We provide one alternative to meta-analysis and multiple imputation by developing a method that statistically equates similar but distinct manifest metrics into a set of empirically derived metrics that can be used for analysis across all datasets.


Assuntos
Big Data , Biologia Computacional/métodos , Conjuntos de Dados como Assunto/normas , Software , Confiabilidade dos Dados , Análise Fatorial
5.
Front Genet ; 10: 494, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178898

RESUMO

Background: Chronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study. Methods: We assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity. Results: The GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry. Conclusion: Our genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations.

6.
Genet Med ; 21(4): 798-812, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30655598

RESUMO

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.


Assuntos
Doenças Genéticas Inatas/genética , Heterogeneidade Genética , Genoma Humano/genética , Genômica/tendências , Bases de Dados Genéticas , Predisposição Genética para Doença , Humanos , National Institutes of Health (U.S.) , Linhagem , Estados Unidos , Sequenciamento Completo do Exoma/métodos
7.
PLoS One ; 14(12): e0226771, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31891604

RESUMO

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.


Assuntos
Afro-Americanos/genética , Aterosclerose/genética , Pleiotropia Genética , Metagenômica , Fenômica , Idoso , Estudos Epidemiológicos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.


Assuntos
Variação Biológica da População/genética , Menarca/genética , Menopausa/genética , Fatores Etários , Alelos , Variação Biológica da População/etnologia , Feminino , Loci Gênicos/genética , Genótipo , Humanos , Menarca/etnologia , Menopausa/etnologia , Fenótipo , Polimorfismo de Nucleotídeo Único
9.
PLoS One ; 13(3): e0194233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29529098

RESUMO

Despite much progress, few genetic findings for schizophrenia have been assessed by functional validation experiments at the molecular level. We previously reported evidence for genetic linkage of broadly defined schizophrenia to chromosome 17q25 in a sample of 24 multiplex families. 2,002 SNPs under this linkage peak were analyzed for evidence of linkage disequilibrium using the posterior probability of linkage (PPL) framework. SNP rs1060120 produced the strongest evidence for association, with a PPLD|L score of 0.21. This SNP is located within the 3'UTR of the histone gene H3F3B and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to H3F3B transcripts would be altered by the allelic variants of rs1060120. We used dual luciferase assays to experimentally validate this interaction. The rs1060120 A allele significantly reduced luciferase expression, indicating a stronger interaction with miR-616 than the G allele (p = 0.000412). These results provide functional validation that this SNP could alter schizophrenia epigenetic mechanisms thereby contributing to schizophrenia-related disease risk.


Assuntos
Sítios de Ligação , Histonas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA Mensageiro/genética , Esquizofrenia/genética , Regiões 3' não Traduzidas , Alelos , Expressão Gênica , Genes Reporter , Estudos de Associação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Fenótipo , Esquizofrenia/diagnóstico
11.
Diabetologia ; 60(12): 2384-2398, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28905132

RESUMO

AIMS/HYPOTHESIS: Elevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies. METHODS: A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation. RESULTS: Previously reported SNP associations were significantly replicated (p ≤ 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513. CONCLUSIONS/INTERPRETATION: These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries. DATA AVAILABILITY: The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Jejum/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Masculino , Polimorfismo de Nucleotídeo Único/genética
12.
Nat Genet ; 49(7): 1113-1119, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530674

RESUMO

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.


Assuntos
Artérias/patologia , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Aterosclerose/genética , Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Metabolismo Energético/genética , Feminino , Predisposição Genética para Doença , Genótipo , Código das Histonas , Humanos , Masculino , Músculo Liso Vascular/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco
13.
Behav Genet ; 47(2): 193-201, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27826669

RESUMO

Auditory detection thresholds for certain frequencies of both amplitude modulated (AM) and frequency modulated (FM) dynamic auditory stimuli are associated with reading in typically developing and dyslexic readers. We present the first behavioral and molecular genetic characterization of these two auditory traits. Two extant extended family datasets were given reading tasks and psychoacoustic tasks to determine FM 2 Hz and AM 20 Hz sensitivity thresholds. Univariate heritabilities were significant for both AM (h 2  = 0.20) and FM (h 2  = 0.29). Bayesian posterior probability of linkage (PPL) analysis found loci for AM (12q, PPL = 81 %) and FM (10p, PPL = 32 %; 20q, PPL = 65 %). Bivariate heritability analyses revealed that FM is genetically correlated with reading, while AM was not. Bivariate PPL analysis indicates that FM loci (10p, 20q) are not also associated with reading.


Assuntos
Limiar Auditivo/fisiologia , Dislexia/genética , Leitura , Estimulação Acústica , Teorema de Bayes , Dislexia/psicologia , Família , Feminino , Genética Comportamental/métodos , Humanos , Masculino , Biologia Molecular/métodos , Linhagem
14.
Heart Rhythm ; 14(4): 572-580, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27988371

RESUMO

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance. OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry. METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis. RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10-5) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs. CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.


Assuntos
Afro-Americanos/genética , Sistema de Condução Cardíaco , Hispano-Americanos/genética , Síndrome do QT Longo , Eletrocardiografia/métodos , Estudo de Associação Genômica Ampla , Sistema de Condução Cardíaco/fisiologia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Desequilíbrio de Ligação , Síndrome do QT Longo/etnologia , Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência , Estados Unidos
15.
PLoS One ; 11(12): e0167758, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27973554

RESUMO

Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease.


Assuntos
Grupos Étnicos/genética , Variação Genética , Genoma Humano , Genômica/métodos , Alelos , Antropometria , Mapeamento Cromossômico , Exoma , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Mutação , Estados Unidos
16.
PLoS One ; 11(10): e0164132, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27736895

RESUMO

Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10-9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans-populations that are understudied for hypertension genetic risk factors.


Assuntos
Afro-Americanos/genética , Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Locos de Características Quantitativas , Variação Genética , Humanos , Proteínas do Tecido Nervoso/genética , Canais de Potássio de Domínios Poros em Tandem/genética , RNA Longo não Codificante/genética
17.
Hum Mol Genet ; 25(19): 4350-4368, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27577874

RESUMO

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.


Assuntos
Doenças Cardiovasculares/genética , Estudo de Associação Genômica Ampla , Ventrículos do Coração/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Afro-Americanos/genética , Alelos , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Eletrocardiografia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Masculino , Miocárdio/patologia , Polimorfismo de Nucleotídeo Único/genética
19.
Hum Mol Genet ; 25(24): 5500-5512, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28426890

RESUMO

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Estudo de Associação Genômica Ampla , Lipídeos/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Afro-Americanos/genética , Apolipoproteína A-V/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Hispano-Americanos/genética , Humanos , Índios Norte-Americanos/genética , Lipase Lipoproteica/genética , Masculino , Triglicerídeos/genética
20.
Clin Ther ; 38(1): 204-10, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26686826

RESUMO

PURPOSE: Antibiotic dosing in obese surgical patients has not been adequately evaluated. The objective of this study was to identify whether currently prescribed doses of cefoxitin achieve adequate and sustained plasma and tissue concentrations in obese patients undergoing sleeve gastrectomy. METHODS: A prospective evaluation of plasma and tissue cefoxitin concentrations in patients undergoing sleeve gastrectomy was performed. On the day of the surgical procedure, venous blood samples (5 mL) were collected just before cefoxitin administration and then at 5, 30, 60, 120, and 240 minutes after dose administration. In addition, subcutaneous adipose tissue was collected from the surgical site at the time of surgical incision and at closure. Cefoxitin concentrations in the collected samples were quantified by using an HPLC-ultraviolet method. A standard noncompartmental analysis was performed for each individual cefoxitin plasma concentration-time profile. In addition, the ratio of tissue to plasma concentration was calculated for all patients. FINDINGS: Plasma and tissue pharmacokinetics of cefoxitin were evaluated in 6 patients undergoing sleeve gastrectomy. The mean age and BMI were 48.7 (6.2) years and 42.8 (7.1) kg/m(2), respectively. At the time of surgical closure, subcutaneous adipose tissue concentrations of cefoxitin were subtherapeutic (<8 µg/mL) in all evaluated patients. IMPLICATIONS: Current dosing strategies for cefoxitin in obese surgical patients may be inadequate, and there is an urgent need to define the appropriate dosage.


Assuntos
Antibacterianos/farmacocinética , Antibioticoprofilaxia , Cefoxitina/farmacocinética , Dermatopatias Bacterianas/prevenção & controle , Infecções dos Tecidos Moles/prevenção & controle , Gordura Subcutânea/metabolismo , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Índice de Massa Corporal , Cefoxitina/administração & dosagem , Cefoxitina/sangue , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/cirurgia , Estudos Prospectivos
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