Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
2.
Rinsho Shinkeigaku ; 2021 Nov 18.
Artigo em Japonês | MEDLINE | ID: mdl-34789630

RESUMO

An 82-year-old man presented with subacute bilateral lower limb paralysis, deep sensory disturbance, and vesico-rectal disturbance. MRI of the spinal cord revealed a large gray matter-dominant lesion extending from the medulla oblongata to the lower thoracic spinal cord. The patient was treated with steroid-pulse therapy for myelitis, but without symptomatic improvement. A spinal cord biopsy was performed for treatment-resistant myelopathy, and histopathology revealed a diffuse large B-cell lymphoma, that was diagnosed as a primary intramedullary spinal cord lymphoma because systemic examination didn't show any other findings suggestive of malignant lymphoma. A spinal cord biopsy is necessary for the definitive diagnosis of this disease, but in the case of poor response to treatment and a progressive course, intramedullary malignant lymphoma should be considered if there is a persistent elevation of CSF IL-10 or a prolonged contrast effect.

3.
Int J Epidemiol ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669934

RESUMO

BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

4.
Nat Genet ; 53(10): 1415-1424, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594039

RESUMO

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Sistema ABO de Grupos Sanguíneos/genética , Bancos de Espécimes Biológicos , Loci Gênicos , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Complexo Principal de Histocompatibilidade/genética , Metanálise como Assunto , Mutação/genética , Fenótipo
5.
Nat Genet ; 53(10): 1504-1516, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34611364

RESUMO

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.


Assuntos
Variação Genética , Genética Populacional , Infecções por HIV/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Mapeamento Físico do Cromossomo , Alelos , Aminoácidos/genética , Frequência do Gene/genética , HIV-1/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Padrões de Referência , Seleção Genética , Carga Viral
6.
Cell ; 184(20): 5247-5260.e19, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34534445

RESUMO

3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

8.
Nat Genet ; 53(8): 1166-1176, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34326544

RESUMO

Effective interpretation of genome function and genetic variation requires a shift from epigenetic mapping of cis-regulatory elements (CREs) to characterization of endogenous function. We developed hybridization chain reaction fluorescence in situ hybridization coupled with flow cytometry (HCR-FlowFISH), a broadly applicable approach to characterize CRISPR-perturbed CREs via accurate quantification of native transcripts, alongside CRISPR activity screen analysis (CASA), a hierarchical Bayesian model to quantify CRE activity. Across >325,000 perturbations, we provide evidence that CREs can regulate multiple genes, skip over the nearest gene and display activating and/or silencing effects. At the cholesterol-level-associated FADS locus, we combine endogenous screens with reporter assays to exhaustively characterize multiple genome-wide association signals, functionally nominate causal variants and, importantly, identify their target genes.


Assuntos
Hibridização in Situ Fluorescente/métodos , Sequências Reguladoras de Ácido Nucleico , Proteínas Adaptadoras de Transdução de Sinal/genética , Teorema de Bayes , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Desoxirribonuclease I/genética , Desoxirribonuclease I/metabolismo , Ácidos Graxos Dessaturases/genética , Citometria de Fluxo , Fator de Transcrição GATA1/genética , Humanos , Células K562 , Proteínas com Domínio LIM/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas , RNA Guia
9.
Nat Commun ; 12(1): 3394, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099641

RESUMO

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants' effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.


Assuntos
Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , Locos de Características Quantitativas , Aprendizado de Máquina Supervisionado , Adulto , Estudos de Coortes , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Polimorfismo de Nucleotídeo Único
11.
Nat Genet ; 53(5): 663-671, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33888908

RESUMO

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10-36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.


Assuntos
Viés , Caracteres Sexuais , Adulto , Artefatos , Bancos de Espécimes Biológicos , Cromossomos Humanos/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra , Reino Unido
12.
Nat Commun ; 12(1): 1098, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597505

RESUMO

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.


Assuntos
Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Seleção Genética , Algoritmos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Genômica/métodos , Haplótipos/genética , Humanos , Modelos Genéticos
14.
Nat Genet ; 53(2): 195-204, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462486

RESUMO

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African-European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Modelos Genéticos , Software , Colesterol/sangue , Colesterol/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Haplótipos/genética , Proteínas de Homeodomínio/genética , Humanos , Lipídeos/sangue , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
15.
Ann Rheum Dis ; 79(10): 1305-1309, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32737115

RESUMO

OBJECTIVES: The genetic background of rheumatoid arthritis-interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans. METHODS: We performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern. RESULTS: We identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at RPA3-UMAD1, OR=2.04, 95% CI 1.59 to 2.60, p=1.5×10-8). Subsequent stratified analysis based on the CT image patterns demonstrated that the effect size of the RA-ILD risk allele (rs12702634-C) was large with the UIP pattern (OR=1.86, 95% CI 0.97 to 3.58, p=0.062) and the probable UIP pattern (OR=2.26, 95% CI 1.36 to 3.73, p=0.0015). CONCLUSION: We revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at RPA3-UMAD1 was relatively high in the CT image patterns related to fibrosis. Our study should contribute to elucidation of the complicated aetiology of RA-ILD.


Assuntos
Artrite Reumatoide/genética , Proteínas de Ligação a DNA/genética , Doenças Pulmonares Intersticiais/genética , Artrite Reumatoide/complicações , Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Doenças Pulmonares Intersticiais/complicações , RNA Antissenso/genética
16.
Nat Genet ; 52(7): 669-679, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32514122

RESUMO

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Variação Genética , Humanos , Padrões de Herança , Japão , Masculino , Fatores Sexuais , Fatores de Transcrição/genética
17.
Nat Med ; 26(4): 542-548, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251405

RESUMO

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks1, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted2. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], Pmeta = 3.9 × 10-13) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10-86). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (Pheterogeneity = 9.5 × 10-8 for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Marcadores Genéticos , Estudo de Associação Genômica Ampla/métodos , Longevidade/genética , Herança Multifatorial/genética , Adulto , Fatores Etários , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Finlândia/epidemiologia , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Hipertensão/genética , Hipertensão/mortalidade , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/mortalidade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Reino Unido/epidemiologia
18.
Nat Commun ; 11(1): 1237, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144282

RESUMO

Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.


Assuntos
Doenças Autoimunes/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Linhagem Celular Tumoral , Predisposição Genética para Doença , Variação Genética/imunologia , Haplótipos/genética , Haplótipos/imunologia , Humanos , Desequilíbrio de Ligação , Herança Multifatorial/imunologia , Estudo de Prova de Conceito
20.
Nat Commun ; 11(1): 1569, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218440

RESUMO

The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Genética Populacional , Redução Dimensional com Múltiplos Fatores , Herança Multifatorial/genética , Sequência de Bases , Bancos de Espécimes Biológicos , Humanos , Japão , Fenótipo , Análise de Componente Principal , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...