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1.
Nat Med ; 27(1): 66-72, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33432171

RESUMO

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.


Assuntos
Registros Eletrônicos de Saúde , Exoma , Genótipo , Fenótipo , Idoso , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
2.
EBioMedicine ; 61: 103062, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33096487

RESUMO

BACKGROUND: Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated inflammation is implicated in the pathophysiology of T2D. METHODS: We performed a meta-analysis of 15 prospective studies to investigate associations between IL-6 levels and incident T2D including 5,421 cases and 31,562 non-cases. We also estimated the association of a loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R), previously shown to mimic the effects of IL-6R inhibition, in a large trans-ethnic meta-analysis of six T2D case-control studies including 260,614 cases and 1,350,640 controls. FINDINGS: In a meta-analysis of 15 prospective studies, higher levels of IL-6 (per log pg/mL) were significantly associated with a higher risk of incident T2D (1·24 95% CI, 1·17, 1·32; P = 1 × 10-12). In a trans-ethnic meta-analysis of 260,614 cases and 1,350,640 controls, the IL6R Asp358Ala missense variant was associated with lower odds of T2D (OR, 0·98; 95% CI, 0·97, 0·99; P = 2 × 10-7). This association was not due to diagnostic misclassification and was consistent across ethnic groups. IL-6 levels mediated up to 5% of the association between higher body mass index and T2D. INTERPRETATION: Large-scale human prospective and genetic data provide evidence that IL-6 mediated inflammation is implicated in the etiology of T2D but suggest that the impact of this pathway on disease risk in the general population is likely to be small. FUNDING: The EPICNorfolk study has received funding from the Medical Research Council (MRC) (MR/N003284/1, MC-UU_12015/1 and MC_PC_13048) and Cancer Research UK (C864/A14136). The Fenland Study is funded by the MRC (MC_UU_12015/1 and MC_PC_13046).

3.
PLoS Genet ; 16(6): e1008725, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32603359

RESUMO

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.


Assuntos
Asma/genética , Eczema/genética , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Sazonal/genética , Adolescente , Adulto , Idade de Início , Idoso , Asma/patologia , Criança , Eczema/patologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/patologia
4.
Eur Respir J ; 56(4)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32513781

RESUMO

Viral respiratory infections are usually benign but can trigger asthma exacerbations. The factors associated with upper respiratory tract infection (cold) frequency are not fully understood, nor is it clear whether such factors differ between women and men.To determine which immunological and clinical variables associate with the frequency of self-reported respiratory infections (colds), 150 asthma cases and 151 controls were recruited. Associations between antiviral immune response variables: toll-like receptor (TLR)7/8 gene expression, plasmacytoid dendritic cell (pDC) numbers and interferon-α, tumour necrosis factor and interleukin-12 production, and asthma were then examined that might explain cold frequency.People with asthma cases reported more colds per year (median 3 versus 2; p<0.001) and had lower baseline TLR7 gene expression (odds ratio 0.12; p=0.02) than controls. Associations between many variables and cold frequency differed between women and men. In women, high blood neutrophil counts (ß=0.096, p=0.002), and younger age (ß=-0.017, p<0.001), but not exposure to children, were independently associated with more frequent colds. In men, low TLR7 expression (ß=-0.96, p=0.041) and high CLEC4C gene expression (a marker of pDC; ß=0.88, p=0.008) were independently associated with more frequent colds. Poor asthma symptom control was independently associated with reduced TLR8 gene expression (ß=-1.4, p=0.036) and high body mass index (ß=0.041, p=0.004).Asthma, age and markers of inflammation and antiviral immunity in peripheral blood are associated with frequent colds. Interestingly, the variables associated with cold frequency differed between women and men.

5.
Twin Res Hum Genet ; 23(2): 100, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32482193

RESUMO

Twins, data and emails. Some of the words that first come to mind when I think of Nick. Lots of twins. With lots of data. And short single-finger-typed emails. And great wine. Well, it works, there is no doubt. That's how I ended up in Australia, working on asthma genetics.

6.
Allergy ; 75(2): 336-345, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31321783

RESUMO

BACKGROUND: Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome-wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)-induced allergic sensitization and allergic airway inflammation. METHODS: Pag1-deficient (Pag1-/- ) and wild-type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti-CD4 antibody) and adoptive transfer studies. RESULTS: Type 2 inflammation (eosinophilia, eotaxin-2 expression, IL-4/IL-5/IL-13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1-/- mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high-mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte-derived dendritic cell numbers in the mediastinal lymph nodes, and increased T-helper type 2 (TH 2)-cell differentiation. CD4+ T-cell depletion studies or the adoptive transfer of WT OVA-specific CD4+ T cells to WT or Pag1-/- recipients demonstrated that the heightened propensity for TH 2-cell differentiation was both T cell intrinsic and extrinsic. CONCLUSION: PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH 2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

7.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
8.
Am J Hum Genet ; 104(4): 665-684, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929738

RESUMO

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.


Assuntos
Asma/genética , Predisposição Genética para Doença , Adolescente , Adulto , Idade de Início , Alelos , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipersensibilidade , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Reino Unido , Adulto Jovem
9.
J Allergy Clin Immunol ; 143(2): 691-699, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29679657

RESUMO

BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses. CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.


Assuntos
Asma/genética , Eczema/genética , Genótipo , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Antígeno 2 Relacionado a Fos/genética , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Interleucina-27/genética , Polimorfismo de Nucleotídeo Único , Risco , Equilíbrio Th1-Th2/genética
10.
Schizophr Bull ; 45(6): 1251-1256, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30452727

RESUMO

Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.


Assuntos
Neoplasias da Mama/genética , Esquizofrenia/genética , Neoplasias da Mama/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Paridade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/epidemiologia , Fumar/epidemiologia
11.
J Alzheimers Dis ; 64(1): 49-54, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29865051

RESUMO

Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.


Assuntos
Apolipoproteínas E/genética , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/genética , Estudos de Coortes , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
14.
Nat Genet ; 50(1): 42-53, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29273806

RESUMO

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.


Assuntos
Asma/genética , Elementos Facilitadores Genéticos , Alelos , Asma/etnologia , Asma/imunologia , Epigênese Genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Código das Histonas , Humanos , Leucócitos/metabolismo , Fenótipo , Regiões Promotoras Genéticas , Rinite Alérgica Sazonal/genética , Risco
15.
J Allergy Clin Immunol ; 141(3): 991-1001, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29030101

RESUMO

BACKGROUND: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. OBJECTIVE: We sought to investigate genetic susceptibility to PA. METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.


Assuntos
Epigênese Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Hipersensibilidade a Amendoim/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Feminino , Humanos , Masculino , Hipersensibilidade a Amendoim/epidemiologia , Hipersensibilidade a Amendoim/metabolismo , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Fatores de Risco , alfa Catenina/biossíntese , alfa Catenina/genética
16.
Nat Genet ; 49(12): 1752-1757, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083406

RESUMO

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.


Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Sci Rep ; 7(1): 5623, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28717140

RESUMO

The involvement of the immune system, particularly the role of T-cells, in sarcoidosis is unclear. The existence of higher CD4+ T-cells and increased CD4/CD8 ratio may indicate a pathogenic role of T-cells in the disease. In this study, we quantified the contribution of T-cells associated variants and of CD4/CD8 ratio in sarcoidosis phenotypes, Löfgren's syndrome (LS) and non- Löfgren's syndrome (non-LS). We employed a polygenic-based approach using genome-wide association studies results on relative levels of T-cells in healthy individuals to measure the genetic contribution of T-cells in sarcoidosis entities. Results revealed that the genetic architecture of LS is highly influenced by genetic variants associated with CD8+ T-cells and CD4/CD8 ratio, explaining up to 7.94% and 6.49% of LS variation, respectively; whereas, the genetic architecture of non-LS is minimally influenced by T-cells, explaining a phenotypic variation of <1%. Moreover, pleiotropy assessment between T-cells and LS/non-LS associated-variants led to the discovery of highly scored pathway maps that shared common factors related to antigen presentation and T-cell regulatory mechanisms. Differences in significant polygenic scores, presence of pleiotropy, and distinct genetic factors provide further insights on how genetic variants and genes associated with relative levels of T-cell subtypes contribute differently to sarcoidosis phenotypes.


Assuntos
Cadeias HLA-DRB1/genética , Polimorfismo de Nucleotídeo Único , Sarcoidose/genética , Linfócitos T/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
18.
J Alzheimers Dis ; 59(1): 85-99, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28582860

RESUMO

Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.


Assuntos
Doença de Alzheimer/sangue , Ferritinas/sangue , Ferro/sangue , Transferrina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Estudos de Coortes , Planejamento em Saúde Comunitária , Feminino , Estudos de Associação Genética/estatística & dados numéricos , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
19.
J Allergy Clin Immunol ; 140(3): 771-781, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28188724

RESUMO

BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.


Assuntos
Doenças Autoimunes/genética , Hipersensibilidade/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único
20.
J Allergy Clin Immunol ; 139(4): 1148-1157, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27554816

RESUMO

BACKGROUND: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. OBJECTIVE: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. METHODS: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. RESULTS: We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. CONCLUSION: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.


Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Nucleotídeos/genética , Software , Animais , Variação Genética/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , ATPases Mitocondriais Próton-Translocadoras/genética , Nucleotídeos/biossíntese , Locos de Características Quantitativas/genética , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2Y/genética
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