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1.
Nat Commun ; 10(1): 3009, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285442

RESUMO

Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.


Assuntos
Genes Ligados ao Cromossomo X/genética , Loci Gênicos/genética , Variação Genética/genética , Herança Multifatorial/genética , Inativação do Cromossomo X/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Genéticos , Fenótipo , Fatores Sexuais
2.
Nature ; 571(7763): 107-111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217582

RESUMO

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.


Assuntos
Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genética
3.
Nat Commun ; 10(1): 2128, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086182

RESUMO

Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Genoma Bacteriano/genética , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Análise Mutacional de DNA , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Regiões Promotoras Genéticas/genética , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Sequenciamento Completo do Genoma
4.
Medicine (Baltimore) ; 98(20): e15247, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096432

RESUMO

The aim of the current study was to investigate the expression of long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) in allergic rhinitis (AR) patients, and to further explore the association of lncRNA ANRIL expression with AR risk, severity, and inflammation.In this case-control study, 96 AR patients and 96 non-atopic obstructive snoring patients who underwent adenoid surgery were consecutively recruited. Disease severity of AR patients was assessed via individual nasal symptom score (INSS) and total nasal symptom score (TNSS). Nasal mucosa samples were collected from AR patients and controls, then lncRNA ANRIL and inflammatory cytokine levels were assessed via quantitative polymerase chain reaction.LncRNA ANRIL expression was increased in AR patients (3.605 [1.763-4.981]) compared with controls (1.183 [0.438-2.985]), and it well distinguished AR patients from controls with an area under curve of 0.746 (95% CI: 0.679-0.814). Correlation analyses revealed that lncRNA ANRIL expression was positively associated with itching score and congestion score, while it was not associated with nasal rhinorrhea score or sneezing score. Besides, lncRNA ANRIL was also positively correlated with TNSS, tumor necrosis factor α, interleukin (IL)-4, IL-6, IL-13, and IL-17, while negatively associated with IL-10 and interferon-γ. And no association of lncRNA ANRIL expression with IL-1ß, IL-5, or IL-8 expression was discovered.LncRNA ANRIL expression correlates with increased AR risk, severity, and inflammation, implying that lncRNA ANRIL might be involved in the pathogenesis of AR.


Assuntos
Loci Gênicos/genética , Inflamação/metabolismo , Mucosa Nasal/metabolismo , RNA Longo não Codificante/genética , Rinite Alérgica/genética , Adolescente , Adulto , Estudos de Casos e Controles , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-5/metabolismo , Interleucina-8/metabolismo , Masculino , Mucosa Nasal/patologia , Fragmentos de Peptídeos/metabolismo , Rinite Alérgica/patologia , Rinite Alérgica/cirurgia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
5.
Parasitol Res ; 118(7): 2305-2310, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079254

RESUMO

Giardia duodenalis is an important zoonotic intestinal protozoan of animals and humans. We collected 450 faecal specimens from four age groups (pre-weaned piglets, weaned piglets, juveniles, adults) of Zangxiang pigs from Shaanxi and Qinghai provinces, to investigate the prevalence and genetic diversity of G. duodenalis at the ß-giardin (bg), triosephosphate isomerase (tpi) and glutamate dehydrogenase (gdh) loci using nested PCRs in the present study. A total of 28 faecal samples were positive for presence of G. duodenalis, with an overall prevalence of 6.2%. Giardia duodenalis was detected in pigs from all age groups and in both investigated provinces. Significant differences (P < 0.0001) in prevalence were observed among the four age groups with prevalence decreasing with age. Sequence analysis indicated existence of genetic diversity of G. duodenalis isolates from Zangxiang pigs, with 4, 2 and 4 haplotypes at the bg, tpi and gdh loci, respectively. Two assemblages were identified, including the zoonotic assemblage B and assemblage E, with the latter as the predominant assemblage found in both locations and all age groups except adults. The present study expanded the host range of G. duodenalis and provided fundamental data for controlling G. duodenalis infection in Zangxiang pigs.


Assuntos
Variação Genética , Giardia lamblia/genética , Giardíase/veterinária , Especificidade de Hospedeiro , Doenças dos Suínos/parasitologia , Animais , China/epidemiologia , Fezes/parasitologia , Loci Gênicos/genética , Genótipo , Giardia lamblia/isolamento & purificação , Giardíase/epidemiologia , Giardíase/parasitologia , Glutamato Desidrogenase/genética , Humanos , Tipagem de Sequências Multilocus/veterinária , Reação em Cadeia da Polimerase/veterinária , Prevalência , Proteínas de Protozoários/genética , Suínos , Doenças dos Suínos/epidemiologia , Triose-Fosfato Isomerase/genética , Desmame , Zoonoses
6.
Nat Commun ; 10(1): 1598, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962441

RESUMO

Understanding the impact of guide RNA (gRNA) and genomic locus on CRISPR-Cas9 activity is crucial to design effective gene editing assays. However, it is challenging to profile Cas9 activity in the endogenous cellular environment. Here we leverage our TRIP technology to integrate ~ 1k barcoded reporter genes in the genomes of mouse embryonic stem cells. We target the integrated reporters (IRs) using RNA-guided Cas9 and characterize induced mutations by sequencing. We report that gRNA-sequence and IR locus explain most variation in mutation efficiency. Predominant insertions of a gRNA-specific nucleotide are consistent with template-dependent repair of staggered DNA ends with 1-bp 5' overhangs. We confirm that such staggered ends are induced by Cas9 in mouse pre-B cells. To explain observed insertions, we propose a model generating primarily blunt and occasionally staggered DNA ends. Mutation patterns indicate that gRNA-sequence controls the fraction of staggered ends, which could be used to optimize Cas9-based insertion efficiency.


Assuntos
Sistemas CRISPR-Cas/genética , DNA/genética , Edição de Genes/métodos , RNA Guia/genética , Animais , Linhagem Celular , Análise Mutacional de DNA , Genes Reporter/genética , Loci Gênicos/genética , Vetores Genéticos/genética , Camundongos , Células-Tronco Embrionárias Murinas , Taxa de Mutação , Plasmídeos/genética
7.
Hum Genet ; 138(6): 601-611, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968251

RESUMO

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.


Assuntos
Ossos Faciais/metabolismo , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Crânio/metabolismo , Sequenciamento Completo do Exoma/métodos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Anormalidades Craniofaciais/etnologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Ossos Faciais/anatomia & histologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Crânio/anatomia & histologia
8.
Leg Med (Tokyo) ; 37: 95-102, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30831559

RESUMO

The unknown origin of DNA samples derived from crime scenes generates a considerable amount of uncertainty, as do unexpected short tandem repeat (STR) results caused by sample mix-ups, contamination, medical interventions, and transgender individuals (broad meaning). Genetic abnormalities such as somatic/germline mutations, mosaicism or chimerism, sex reversal cases, aneuploidies, and chromosomal structural rearrangements are also possible causes of such results. The evidence offered by the present study suggested that additional DYS385 alleles, as seen in mixed stain samples and in the potentially single-source DNA profile of a female, originated from the female DNA source only. For the case reported here, we propose an interchromosomal insertion hypothesis, in which a 768-kb segment including the P4 palindrome of the azoospermia factor (AZFb) region was deleted from the Y chromosome and inserted into the X chromosome or an autosome during male meiosis. Y-SNP data points from the AccuID platform and in-house PCR assays narrowed down the expected length of the target region. Bioinformatics analysis followed by whole genome amplification and whole genome sequencing showed that a 529-kb segment including the P4 palindrome (HSFY/DYS385)/DYS460 region from the female sample mapped to the Y reference sequence (GRCh37). To our knowledge, the interchromosomal insertional translocation event was identified as an unknown type of genomic rearrangement in the forensic genetic field.


Assuntos
Azoospermia/genética , Cromossomos Humanos Y/genética , Cromossomos Humanos/genética , Genética Forense/métodos , Técnicas de Genotipagem/métodos , Sequências Repetidas Invertidas/genética , Repetições de Microssatélites/genética , Análise para Determinação do Sexo/métodos , Translocação Genética/genética , Alelos , Cromossomos Humanos X/genética , Feminino , Loci Gênicos/genética , Humanos , Masculino , Meiose/genética , Sequenciamento Completo do Genoma
9.
Proc Natl Acad Sci U S A ; 116(13): 6130-6139, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30867287

RESUMO

We have identified regulatory mechanisms in which an RNA transcript forms a DNA duplex·RNA triple helix with a gene or one of its regulatory elements, suggesting potential auto-regulatory mechanisms in vivo. We describe an interaction at the human ß-globin locus, in which an RNA segment embedded in the second intron of the ß-globin gene forms a DNA·RNA triplex with the HS2 sequence within the ß-globin locus control region, a major regulator of globin expression. We show in human K562 cells that the triplex is stable in vivo. Its formation causes displacement from HS2 of major transcription factors and RNA Polymerase II, and consequently in loss of factors and polymerase that bind to the human ε- and γ-globin promoters, which are activated by HS2 in K562 cells. This results in reduced expression of these genes. These effects are observed when a small length of triplex-forming RNA is introduced into cells, or when a full-length intron-containing human ß-globin transcript is expressed. Related results are obtained in human umbilical cord blood-derived erythroid progenitor-2 cells, in which ß-globin expression is similarly affected by triplex formation. These results suggest a model in which RNAs conforming to the strict sequence rules for DNA·RNA triplex formation may participate in feedback regulation of genes in cis.


Assuntos
DNA/metabolismo , RNA/metabolismo , Globinas beta/metabolismo , DNA/química , DNA/genética , Loci Gênicos/genética , Humanos , Células K562 , Conformação de Ácido Nucleico , RNA/química , RNA/genética , RNA Polimerase II/metabolismo , Transcrição Genética , Globinas beta/genética
10.
Nat Genet ; 51(3): 414-430, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30820047

RESUMO

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aß processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Imunidade/genética , Lipídeos/genética , Proteínas tau/genética , Idoso , Estudos de Casos e Controles , Feminino , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Metabolismo dos Lipídeos/genética , Masculino
11.
Nat Commun ; 10(1): 1030, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833571

RESUMO

Carpal tunnel syndrome (CTS) is a common and disabling condition of the hand caused by entrapment of the median nerve at the level of the wrist. It is the commonest entrapment neuropathy, with estimates of prevalence ranging between 5-10%. Here, we undertake a genome-wide association study (GWAS) of an entrapment neuropathy, using 12,312 CTS cases and 389,344 controls identified in UK Biobank. We discover 16 susceptibility loci for CTS with p < 5 × 10-8. We identify likely causal genes in the pathogenesis of CTS, including ADAMTS17, ADAMTS10 and EFEMP1, and using RNA sequencing demonstrate expression of these genes in surgically resected tenosynovium from CTS patients. We perform Mendelian randomisation and demonstrate a causal relationship between short stature and higher risk of CTS. We suggest that variants within genes implicated in growth and extracellular matrix architecture contribute to the genetic predisposition to CTS by altering the environment through which the median nerve transits.


Assuntos
Síndrome do Túnel Carpal/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Proteínas ADAMTS/genética , Idoso , Mapeamento Cromossômico , Simulação por Computador , Proteínas da Matriz Extracelular/genética , Feminino , Genoma Humano/genética , Genótipo , Humanos , Masculino , Nervo Mediano , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Punho
12.
Nat Commun ; 10(1): 1260, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890710

RESUMO

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Osteoporose/genética , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adulto , Diferenciação Celular/genética , Mapeamento Cromossômico , Feminino , Técnicas de Silenciamento de Genes , Loci Gênicos/genética , Células Hep G2 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas de Membrana/genética , Células-Tronco Mesenquimais , Proteínas de Neoplasias/genética , Osteoblastos/fisiologia , Osteogênese/genética , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Wnt/genética , Adulto Jovem
13.
Parasit Vectors ; 12(1): 102, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867035

RESUMO

BACKGROUND: Giardia duodenalis is an important intestinal protozoan infecting both humans and animals, causing significant public health concern and immeasurable economic losses to animal husbandry. Sheep and goats have been reported as common reservoirs of G. duodenalis, but only a limited amount of information is available for native breeds of these small ruminants in China. The present study investigated the prevalence and multilocus genotypes of G. duodenalis in black-boned sheep and goats, two important native breeds in Yunnan Province, southwestern China. METHODS: Fecal samples were collected from 336 black-boned goats and 325 black-boned sheep from five counties (Meishui, Shanshu, Shilin, Yongsheng and Nanping) of Yunnan Province and the genomic DNA was extracted from these feces. The prevalence of G. duodenalis was determined by the nested PCR targeting the ß-giardin (bg) gene. The assemblages and multilocus genotypes (MLGs) were investigated based on analyses of three genetic loci, i.e. bg, glutamate dehydrogenase (gdh) and triosephosphate isomerase (tpi). RESULTS: Giardia duodenalis infection was detected in both black-boned sheep and goats, and the prevalence of G. duodenalis in black-boned sheep (21.8%, 71/325) was significantly higher (χ2 = 36.63, df = 1, P < 0.001) than that in black-boned goats (4.8%, 16/336). Significant differences in prevalence were also observed in goats and sheep from different counties (χ2 = 39.83, df = 4, P < 0.001) and age groups (χ2 = 97.33, df = 3, P < 0.001). Zoonotic assemblage A and animal-specific assemblage E were identified in both black-boned sheep and goats with the latter as the predominant assemblage. Based on sequences obtained from the three genetic loci (bg, gdh and tpi), 16 MLGs were obtained in black-boned sheep and goats, including 15 MLGs in assemblage E and one MLG in assemblage A. CONCLUSIONS: Our results not only extended the host range of G. duodenalis, but also revealed high genetic variations in G. duodenalis assemblages. The findings of the present study also provide baseline data for preventing and controlling G. duodenalis infection in black-boned sheep and goats in Yunnan Province.


Assuntos
Reservatórios de Doenças/parasitologia , Variação Genética , Giardia lamblia/classificação , Giardíase/parasitologia , Doenças das Cabras/parasitologia , Doenças dos Ovinos/parasitologia , Animais , China/epidemiologia , Fezes/parasitologia , Feminino , Loci Gênicos/genética , Genótipo , Giardia lamblia/genética , Giardia lamblia/isolamento & purificação , Giardíase/epidemiologia , Glutamato Desidrogenase/genética , Doenças das Cabras/epidemiologia , Cabras , Especificidade de Hospedeiro , Humanos , Masculino , Tipagem de Sequências Multilocus , Proteínas de Protozoários/genética , Ovinos , Doenças dos Ovinos/epidemiologia , Triose-Fosfato Isomerase/genética
14.
Nat Genet ; 51(3): 379-386, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718926

RESUMO

To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10-8) with 115 independent signals (P < 5.0 × 10-6), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r2 > 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAFJPN > 0.05 versus MAFEUR < 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells).


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Adulto , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética
15.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
16.
Leg Med (Tokyo) ; 37: 64-66, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30711876

RESUMO

We presented allele frequencies of 27 X-chromosomal short tandem repeats (DXS6807, DXS9902, DXS6795, DXS6810, DXS10076, DXS10077, DXS10078, DXS10162, DXS10163, DXS10164, DXS7132, DXS981, DXS6800, DXS6803, DXS6809, DXS6789, DXS6799, DXS7424, DXS101, DXS7133, GATA172D05, DXS10103, HPRTB, GATA31E08, DXS8377, DXS10147, and DXS7423) obtained from 352 unrelated individuals in Egypt. No deviation from Hardy-Weinberg equilibrium was detected. Two pairs of adjacent loci showed significant linkage disequilibrium. In the principal component analysis plot, the Egyptian data were located between Europe and sub-Saharan Africa, away from Asia.


Assuntos
Cromossomos Humanos X/genética , Frequência do Gene/genética , Repetições de Microssatélites/genética , Polimorfismo Genético/genética , Egito , Feminino , Loci Gênicos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino
17.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
18.
Carbohydr Res ; 473: 36-45, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605786

RESUMO

Streptococcus suis serotypes 7 and 8 are counted among the top six S. suis serotypes causing clinical disease in pigs. Yet, limited information is available on these serotypes. Since S. suis serotyping system is based upon capsular polysaccharide (CPS) antigenicity and the CPS is considered a major virulence factor for encapsulated pathogens, here we determined for the first time the chemical compositions and structures of serotypes 7 and 8 CPSs. Chemical and spectroscopic data gave the following repeating unit sequences: [3)L-Rha(α1-P-2)D-Gal(α1-4)D-GlcA(ß1-3)D-FucNAc4N(α1-]n for serotype 7 and [2)L-Rha(α1-P-4)D-ManNAc(ß1-4)D-Glc(α1-]n for serotype 8. As serotype 8 CPS is identical to Streptococcus pneumoniae type 19F CPS, dot-blot analyses showed a strong reaction of the 19F polysaccharide with reference anti-S. suis serotype 8 rabbit serum. A correlation between S. suis serotypes 7 and 8 sequences and genes of those serotypes' loci encoding putative glycosyltransferases and polymerases responsible for the biosynthesis of the repeating units was tentatively established. Knowledge of CPS structure and composition will contribute to better dissect the role of this bacterial component in the pathogenesis of the disease caused by S. suis serotypes 7 and 8.


Assuntos
Cápsulas Bacterianas/química , Loci Gênicos/genética , Polissacarídeos Bacterianos/biossíntese , Polissacarídeos Bacterianos/química , Streptococcus suis/química , Streptococcus suis/genética , Sequência de Carboidratos , Streptococcus suis/metabolismo
19.
Nat Genet ; 51(2): 245-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643258

RESUMO

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.


Assuntos
Comportamento/fisiologia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudos de Casos e Controles , Feminino , Genética Comportamental/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
20.
Leg Med (Tokyo) ; 37: 25-27, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30599443

RESUMO

The population of Guatemala includes Mestizos (admixed) and different Mayan groups (Native Americans), which have been poorly studied in regards to short tandem repeat (STR) loci used for human identification (HID) purposes. Therefore, 483 unrelated Guatemalan volunteers from one Mestizo and three Mayan populations (Poqomchi, Ixil, and Achi) were analyzed with an AmpFlSTR Identifiler™ kit. Allele frequencies and forensic parameters were obtained for 15 autosomal STRs in these populations. Hardy-Weinberg equilibrium by locus and equilibrium linkage between pair of loci were demonstrated by exact tests in all the studied populations. Larger genetic differentiation probably due to genetic drift effects was observed among the studied Guatemalan Mayan groups than the neighboring Mexican Mayas. In brief, our results validate to use the Identifiler™ kit for HID in three non-previously studied Mayan groups, and one Mestizo population from Guatemala.


Assuntos
Genética Forense/métodos , Técnicas de Genotipagem/métodos , Repetições de Microssatélites/genética , Kit de Reagentes para Diagnóstico , Feminino , Frequência do Gene , Deriva Genética , Ligação Genética , Loci Gênicos/genética , Guatemala/etnologia , Humanos , Desequilíbrio de Ligação , Masculino
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