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1.
Nat Commun ; 10(1): 4788, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636271

RESUMO

Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipids, across distinct time points as well as information on statin usage. We increase effective sample size by an average of two-fold by applying the Covariates for Multi-phenotype Studies (CMS) approach, identifying 588 significant SNP-metabolite associations, including 228 new associations. Our analysis pinpoints a small number of master metabolic regulator genes, balancing the relative proportion of dozens of metabolite levels. We further identify associations to changes in metabolic levels across time as well as genetic interactions with statin at both the master metabolic regulator and genome-wide level.

2.
Am J Hum Genet ; 105(4): 773-787, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564431

RESUMO

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.

3.
PLoS Genet ; 15(4): e1008009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951530

RESUMO

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Fenótipo , Algoritmos , Glicemia/efeitos dos fármacos , Glicemia/genética , Análise por Conglomerados , Simulação por Computador , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/genética , Locos de Características Quantitativas
4.
Nurs Manage ; 50(3): 26-36, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817430
5.
Elife ; 82019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30834892

RESUMO

Correlation among traits is a fundamental feature of biological systems that remains difficult to study. To address this problem, we developed a flexible approach that allows us to identify factors associated with inter-individual variation in correlation. We use data from three human cohorts to study the effects of genetic and environmental variation on correlations among mRNA transcripts and among NMR metabolites. We first show that environmental exposures (infection and disease) lead to a systematic loss of correlation, which we define as 'decoherence'. Using longitudinal data, we show that decoherent metabolites are better predictors of whether someone will develop metabolic syndrome than metabolites commonly used as biomarkers of this disease. Finally, we demonstrate that correlation itself is under genetic control by mapping hundreds of 'correlation quantitative trait loci (QTLs)'. Together, this work furthers our understanding of how and why coordinated biological processes break down, and points to a potential role for decoherence in disease. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

6.
Home Healthc Now ; 37(2): 79-87, 2019 Mar/Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30829785

RESUMO

Evidence-based practice (EBP) is becoming standard in today's healthcare arena and home care organizations are not exempt from integrating evidence into practice to improve patient outcomes. There is a scarcity of research literature that examines the behaviors and attitudes of home healthcare nurses (HHNs) regarding EBP. In this study, a descriptive survey design was used to investigate HHNs' a) information-seeking behaviors when providing nursing care, b) administrative support for EBP (as perceived by HHNs), c) attitudes toward EBP, and d) EBP engagement and confidence in providing EBP nursing care. Self-reported data were collected by internet and paper survey. The survey consisted of a 65-item questionnaire that included the Nurses' Attitudes Toward Evidence-Based Practice Scale, which has previously established validity and reliability. A convenience sample of 95 HHNs participated in the study. Results suggest HHNs' EBP attitudes are positive. A positive and significant relationship was found between attitudes and hours worked (r = 0.21, p = 0.047) and educational level (r = 0.45, p = 0.0001); 95% confidence level. Confidence levels in providing EBP care were moderate, and HHNs did not perceive EBP as an agency priority. HHNs need to be supported and encouraged in the facilitation of EBP, a task made easier when they are knowledgeable about EBP, have confidence in their EBP skills, and have the support of their organizations.


Assuntos
Atitude do Pessoal de Saúde , Competência Clínica , Prática Clínica Baseada em Evidências/normas , Enfermagem Domiciliar/métodos , Relações Enfermeiro-Paciente , Enfermagem Baseada em Evidências/normas , Feminino , Serviços de Assistência Domiciliar/organização & administração , Humanos , Masculino , Autoimagem , Inquéritos e Questionários , Estados Unidos
7.
Nat Commun ; 9(1): 3472, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135520

RESUMO

In the original version of this Article, Supplementary Table 10 contained incorrect primer sequences for the mobility shift assay for SNP rs4776984. These errors have now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.

8.
Nat Commun ; 9(1): 1512, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666371

RESUMO

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi-C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes.

9.
Home Healthc Now ; 36(2): 114-122, 2018 Mar/Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29498991

RESUMO

Evidence-based practice requires access to practice guidelines, research articles, and other resources; however, home healthcare clinicians can face barriers when seeking health information. The purpose of this article is to provide home care clinicians with: a) free resources available on the internet, b) suggestions for searching and evaluating health information found on the internet, and c) opportunities for free continuing education for home healthcare clinicians.


Assuntos
Acesso à Informação , Serviços de Assistência Domiciliar/organização & administração , Internet/estatística & dados numéricos , Informática Médica/educação , Avaliação de Resultados (Cuidados de Saúde) , Prática Clínica Baseada em Evidências/educação , Feminino , Recursos em Saúde , Humanos , Disseminação de Informação , Masculino , Determinação de Necessidades de Cuidados de Saúde , Médicos , Estados Unidos
10.
Bioinformatics ; 34(8): 1313-1320, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29186329

RESUMO

Motivation: Mapping bias causes preferential alignment to the reference allele, forming a major obstacle in allele-specific expression (ASE) analysis. The existing methods, such as simulation and SNP-aware alignment, are either inaccurate or relatively slow. To fast and accurately count allelic reads for ASE analysis, we developed a novel approach, ASElux, which utilizes the personal SNP information and counts allelic reads directly from unmapped RNA-sequence (RNA-seq) data. ASElux significantly reduces runtime by disregarding reads outside single nucleotide polymorphisms (SNPs) during the alignment. Results: When compared to other tools on simulated and experimental data, ASElux achieves a higher accuracy on ASE estimation than non-SNP-aware aligners and requires a much shorter time than the benchmark SNP-aware aligner, GSNAP with just a slight loss in performance. ASElux can process 40 million read-pairs from an RNA-sequence (RNA-seq) sample and count allelic reads within 10 min, which is comparable to directly counting the allelic reads from alignments based on other tools. Furthermore, processing an RNA-seq sample using ASElux in conjunction with a general aligner, such as STAR, is more accurate and still ∼4× faster than STAR + WASP, and ∼33× faster than the lead SNP-aware aligner, GSNAP, making ASElux ideal for ASE analysis of large-scale transcriptomic studies. We applied ASElux to 273 lung RNA-seq samples from GTEx and identified a splice-QTL rs11078928 in lung which explains the mechanism underlying an asthma GWAS SNP rs11078927. Thus, our analysis demonstrated ASE as a highly powerful complementary tool to cis-expression quantitative trait locus (eQTL) analysis. Availability and implementation: The software can be downloaded from https://github.com/abl0719/ASElux. Contact: zmiao@ucla.edu or a5ko@ucla.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

11.
Home Healthc Now ; 35(9): 507-513, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28953541

RESUMO

The number of Asian immigrants has risen dramatically in recent decades, making them the fastest growing immigrant group in the United States. Home healthcare clinicians are expected to meet the healthcare needs of patients regardless of their ethnic or cultural background, but this can be challenging without a basic understanding of the patient's culture. This article is intended to provide information about the cultural traditions and health conditions clinicians may encounter when caring for patients and families who have immigrated to the United States from the top five Asian countries as determined by the U.S. Census, and concludes with resources that home healthcare clinicians can utilize when engaging in patient education.


Assuntos
Grupo com Ancestrais do Continente Asiático , Assistência à Saúde Culturalmente Competente/métodos , Emigrantes e Imigrantes , Enfermagem Domiciliar , China/etnologia , Diversidade Cultural , Cultura , Necessidades e Demandas de Serviços de Saúde , Enfermagem Domiciliar/métodos , Humanos , Índia/etnologia , Coreia (Geográfico)/etnologia , Educação de Pacientes como Assunto , Filipinas/etnologia , Estados Unidos , Vietnã/etnologia
12.
Atherosclerosis ; 264: 58-66, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28772107

RESUMO

BACKGROUND AND AIMS: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). METHODS: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). RESULTS: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. CONCLUSIONS: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs.


Assuntos
Colesterol/sangue , Hiperlipoproteinemia Tipo II/genética , Mutação , Polimorfismo de Nucleotídeo Único , Apolipoproteína B-100/genética , Áustria , Biomarcadores/sangue , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Receptores de LDL/genética , Fatores de Risco , Sequenciamento Completo do Exoma
13.
Am J Hum Genet ; 100(3): 428-443, 2017 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28257690

RESUMO

Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10-8) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.


Assuntos
Doenças Cardiovasculares/genética , Regulação da Expressão Gênica , Síndrome Metabólica/genética , Locos de Características Quantitativas , Gordura Subcutânea/metabolismo , Idoso , Animais , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Reprodutibilidade dos Testes , Transativadores/genética , Transativadores/metabolismo
14.
Arterioscler Thromb Vasc Biol ; 36(7): 1350-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27199446

RESUMO

OBJECTIVE: We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region. APPROACH AND RESULTS: We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856). CONCLUSIONS: The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans.


Assuntos
Cromossomos Humanos Par 18 , Fator 4 Nuclear de Hepatócito/genética , Metabolismo dos Lipídeos/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Idoso , Sítios de Ligação , Finlândia , Genes Reporter , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Células Hep G2 , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/metabolismo , México , Pessoa de Meia-Idade , Fenótipo , Locos de Características Quantitativas , Transcrição Genética , Transfecção , Estados Unidos , Regulação para Cima
15.
Nat Genet ; 48(3): 245-52, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26854917

RESUMO

Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ∼ 3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 new genes significantly associated with obesity-related traits (BMI, lipids and height). Many of these genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits.


Assuntos
Regulação da Expressão Gênica/genética , Obesidade/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética , Animais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Camundongos , Obesidade/patologia , Fenótipo
16.
Stroke ; 46(9): 2445-51, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26251247

RESUMO

BACKGROUND AND PURPOSE: Remote ischemic conditioning (RIC) is a phenomenon in which short periods of nonfatal ischemia in 1 tissue confers protection to distant tissues. Here we performed a longitudinal human pilot study in patients with aneurysmal subarachnoid hemorrhage undergoing RIC by limb ischemia to compare changes in DNA methylation and transcriptome profiles before and after RIC. METHODS: Thirteen patients underwent 4 RIC sessions over 2 to 12 days after rupture of an intracranial aneurysm. We analyzed whole blood transcriptomes using RNA sequencing and genome-wide DNA methylomes using reduced representation bisulfite sequencing, both before and after RIC. We tested differential expression and differential methylation using an intraindividual paired study design and then overlapped the differential expression and differential methylation results for analyses of functional categories and protein-protein interactions. RESULTS: We observed 164 differential expression genes and 3493 differential methylation CpG sites after RIC, of which 204 CpG sites overlapped with 103 genes, enriched for pathways of cell cycle (P<3.8×10(-4)) and inflammatory responses (P<1.4×10(-4)). The cell cycle pathway genes form a significant protein-protein interaction network of tightly coexpressed genes (P<0.00001). CONCLUSIONS: Gene expression and DNA methylation changes in aneurysmal subarachnoid hemorrhage patients undergoing RIC are involved in coordinated cell cycle and inflammatory responses.


Assuntos
Metilação de DNA/fisiologia , Expressão Gênica/fisiologia , Genes cdc/fisiologia , Aneurisma Intracraniano/metabolismo , Precondicionamento Isquêmico/métodos , Hemorragia Subaracnóidea/metabolismo , Adulto , Idoso , Feminino , Humanos , Aneurisma Intracraniano/terapia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Hemorragia Subaracnóidea/terapia , Transcriptoma/fisiologia
17.
PLoS One ; 9(8): e104396, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25116239

RESUMO

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.


Assuntos
Asma/genética , Efeito Fundador , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Alelos , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Frequência do Gene , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Masculino , Ubiquitina-Proteína Ligases Nedd4 , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética , Deleção de Sequência , Ubiquitina-Proteína Ligases/genética
18.
Nat Commun ; 5: 3983, 2014 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-24886709

RESUMO

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.


Assuntos
Hipercolesterolemia/genética , Hipertrigliceridemia/genética , Índios Norte-Americanos/genética , Obesidade/genética , Adulto , Apolipoproteína A-V , Apolipoproteínas A/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 8/genética , Dislipidemias/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Lipase Lipoproteica/genética , Modelos Logísticos , Masculino , México/etnologia , Pessoa de Meia-Idade , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/genética , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 110(33): 13457-62, 2013 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-23884656

RESUMO

We analyzed 83 fully sequenced great ape genomes for mobile element insertions, predicting a total of 49,452 fixed and polymorphic Alu and long interspersed element 1 (L1) insertions not present in the human reference assembly and assigning each retrotransposition event to a different time point during great ape evolution. We used these homoplasy-free markers to construct a mobile element insertions-based phylogeny of humans and great apes and demonstrate their differential power to discern ape subspecies and populations. Within this context, we find a good correlation between L1 diversity and single-nucleotide polymorphism heterozygosity (r(2) = 0.65) in contrast to Alu repeats, which show little correlation (r(2) = 0.07). We estimate that the "rate" of Alu retrotransposition has differed by a factor of 15-fold in these lineages. Humans, chimpanzees, and bonobos show the highest rates of Alu accumulation--the latter two since divergence 1.5 Mya. The L1 insertion rate, in contrast, has remained relatively constant, with rates differing by less than a factor of three. We conclude that Alu retrotransposition has been the most variable form of genetic variation during recent human-great ape evolution, with increases and decreases occurring over very short periods of evolutionary time.


Assuntos
Variação Genética , Genoma/genética , Hominidae/genética , Filogenia , Elementos Alu/genética , Animais , Análise por Conglomerados , Primers do DNA/genética , Genômica , Hominidae/classificação , Humanos , Funções Verossimilhança , Elementos Nucleotídeos Longos e Dispersos/genética , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Especificidade da Espécie
20.
Nat Genet ; 44(11): 1277-81, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23001126

RESUMO

Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity. Using the number of meioses separating each pair of autozygous alleles and the 72 validated heterozygous single-nucleotide variants (SNVs) from 512 Mb of autozygous DNA, we obtained an SNV mutation rate of 1.20 × 10(-8) (95% confidence interval 0.89-1.43 × 10(-8)) mutations per base pair per generation. The mutation rate for bases within CpG dinucleotides (9.72 × 10(-8)) was 9.5-fold that of non-CpG bases, and there was strong evidence (P = 2.67 × 10(-4)) for a paternal bias in the origin of new mutations (85% paternal). We observed a non-uniform distribution of heterozygous SNVs (both newly identified and known) in the autozygous segments (P = 0.001), which is suggestive of mutational hotspots or sites of long-range gene conversion.


Assuntos
Evolução Molecular , Genética Populacional , Taxa de Mutação , Mutação , Alelos , Mapeamento Cromossômico , Genoma Humano , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único
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