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1.
Nature ; 558(7708): 73-79, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29875488

RESUMO

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.


Assuntos
Proteínas Sanguíneas/genética , Genômica , Proteoma/genética , Feminino , Fator de Crescimento de Hepatócito/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Mutação de Sentido Incorreto/genética , Mieloblastina/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas/genética , Vasculite/genética , alfa 1-Antitripsina/genética
2.
Nature ; 547(7662): 173-178, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28658209

RESUMO

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Doenças Inflamatórias Intestinais/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação , Cromatina/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Epigênese Genética/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Proteína Smad3/genética , Fatores de Transcrição/metabolismo , Adulto Jovem
3.
Hum Mol Genet ; 26(21): 4301-4313, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973304

RESUMO

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.


Assuntos
Psoríase/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Psoríase/fisiopatologia , Fatores de Risco , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Sequenciamento do Exoma
4.
Nature ; 491(7422): 119-24, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23128233

RESUMO

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Mycobacterium/imunologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/microbiologia , Doença de Crohn/fisiopatologia , Genoma Humano/genética , Haplótipos/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mycobacterium/patogenicidade , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/microbiologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
5.
PLoS Genet ; 11(2): e1004955, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25671699

RESUMO

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Glicoproteínas de Membrana/genética , Butirofilinas , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
6.
Hum Mol Genet ; 24(R1): R111-9, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26157023

RESUMO

Genome-wide association studies (GWAS) have identified thousands of robust and replicable genetic associations for complex disease. However, the identification of the causal variants that underlie these associations has been more difficult. This problem of fine-mapping association signals predates GWAS, but the last few years have seen a surge of studies aimed at pinpointing causal variants using both statistical evidence from large association data sets and functional annotations of genetic variants. Combining these two approaches can often determine not only the causal variant but also the target gene. Recent contributions include analyses of custom genotyping arrays, such as the Immunochip, statistical methods to identify credible sets of causal variants and the addition of functional genomic annotations for coding and non-coding variation to help prioritize variants and discern functional consequence and hence the biological basis of disease risk.


Assuntos
Mapeamento Cromossômico , Animais , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
7.
Hum Mol Genet ; 21(23): 5185-92, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22914738

RESUMO

Psoriasis is a common, chronic, inflammatory skin disorder. A number of genetic loci have been shown to confer risk for psoriasis. Collectively, these offer an integrated model for the inherited basis for susceptibility to psoriasis that combines altered skin barrier function together with the dysregulation of innate immune pathogen sensing and adap-tive immunity. The major histocompatibility complex (MHC) harbours the psoriasis susceptibility region which exhibits the largest effect size, driven in part by variation contained on the HLA-Cw*0602 allele. However, the resolution of the number and genomic location of potential independent risk loci are hampered by extensive linkage disequilibrium across the region. We leveraged the power of large psoriasis case and control data sets and the statistical approach of conditional analysis to identify potential further association signals distributed across the MHC. In addition to the major loci at HLA-C (P = 2.20 × 10(-236)), we observed and replicated four additional independent signals for disease association, three of which are novel. We detected evidence for association at SNPs rs2507971 (P = 6.73 × 10(-14)), rs9260313 (P = 7.93 × 10(-09)), rs66609536 (P = 3.54 × 10(-07)) and rs380924 (P = 6.24 × 10(-06)), located within the class I region of the MHC, with each observation replicated in an independent sample (P ≤ 0.01). The previously identified locus is close to MICA, the other three lie near MICB, HLA-A and HCG9 (a non-coding RNA gene). The identification of disease associations with both MICA and MICB is particularly intriguing, since each encodes an MHC class I-related protein with potent immunological function.


Assuntos
Predisposição Genética para Doença , Complexo Principal de Histocompatibilidade/genética , Psoríase/genética , Alelos , Loci Gênicos , Estudo de Associação Genômica Ampla , Antígenos HLA-C/genética , Humanos , Polimorfismo de Nucleotídeo Único
8.
Hum Mol Genet ; 21(4): 934-46, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22076443

RESUMO

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 1/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Mapeamento Cromossômico , Biologia Computacional , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Haplótipos , Humanos , Modelos Logísticos , Software
9.
Am J Hum Genet ; 89(3): 432-7, 2011 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-21839423

RESUMO

Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.


Assuntos
Predisposição Genética para Doença/genética , Imunidade Inata/genética , Interleucinas/genética , Modelos Moleculares , Psoríase/genética , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Inata/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Linhagem , Psoríase/imunologia , Análise de Sequência de DNA
10.
PLoS One ; 16(10): e0258316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34673799

RESUMO

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Proliferação de Células , Regulação da Expressão Gênica , Predisposição Genética para Doença , Homozigoto , Humanos , Doenças Inflamatórias Intestinais/patologia , Receptores CXCR3/metabolismo
11.
Schizophr Bull ; 42(5): 1176-84, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27242348

RESUMO

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.


Assuntos
Doenças Autoimunes/genética , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Esquizofrenia/imunologia , Humanos
12.
Nat Genet ; 48(5): 510-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26974007

RESUMO

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.


Assuntos
Colangite Esclerosante/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Pleiotropia Genética , Inflamação/genética , Psoríase/genética , Espondilite Anquilosante/genética , Teorema de Bayes , Doença Crônica , Comorbidade , Heterogeneidade Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Locos de Características Quantitativas
13.
J Rheumatol ; 42(7): 1131-40, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25979711

RESUMO

OBJECTIVE: Genetic variants affect both the development and severity of rheumatoid arthritis (RA). Recent studies have expanded the number of RA susceptibility variants. We tested the hypothesis that these associated with disease severity in a clinical trial cohort of patients with early, active RA. METHODS: We evaluated 524 patients with RA enrolled in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants - 69 single-nucleotide polymorphisms (SNP), 15 HLA-DRB1 alleles, and amino acid polymorphisms in 6 HLA molecule positions - for their associations with progression in Larsen scoring, 28-joint Disease Activity Scores, and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models. RESULTS: HLA variants were associated with joint destruction. The *04:01 SNP (rs660895, p = 0.0003), *04:01 allele (p = 0.0002), and HLA-DRß1 amino acids histidine at position 13 (p = 0.0005) and valine at position 11 (p = 0.0012) significantly associated with radiological progression. This association was only significant in anticitrullinated protein antibody (ACPA)-positive patients, suggesting that while their effects were not mediated by ACPA, they only predicted joint damage in ACPA-positive RA. Non-HLA variants did not associate with radiograph damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNP - rs11889341 (STAT4, p = 0.0001) and rs653178 (SH2B3-PTPN11, p = 0.0004) - associated with HAQ scores over 6-24 months. CONCLUSION: HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Feminino , Estudos de Associação Genética , Genótipo , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Índice de Gravidade de Doença
14.
Nat Commun ; 6: 7001, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25939698

RESUMO

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Psoríase/genética , Proteínas Adaptadoras de Transdução de Sinal , Estudo de Associação Genômica Ampla , Humanos , Proteínas I-kappa B/genética , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Proteínas Nucleares/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo
15.
J Affect Disord ; 155: 81-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24215895

RESUMO

BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto Jovem
16.
PLoS One ; 8(8): e71690, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23990973

RESUMO

Psoriasis is an immune-mediated skin disorder that is inherited as a complex genetic trait. Although genome-wide association scans (GWAS) have identified 36 disease susceptibility regions, more than 50% of the genetic variance can be attributed to a single Major Histocompatibility Complex (MHC) locus, known as PSORS1. Genetic studies indicate that HLA-C is the strongest PSORS1 candidate gene, since markers tagging HLA-Cw*0602 consistently generate the most significant association signals in GWAS. However, it is unclear whether HLA-Cw*0602 is itself the causal PSORS1 allele, especially as the role of SNPs that may affect its expression has not been investigated. Here, we have undertaken an in-depth molecular characterization of the PSORS1 interval, with a view to identifying regulatory variants that may contribute to disease susceptibility. By analysing high-density SNP data, we refined PSORS1 to a 179 kb region encompassing HLA-C and the neighbouring HCG27 pseudogene. We compared multiple MHC sequences spanning this refined locus and identified 144 candidate susceptibility variants, which are unique to chromosomes bearing HLA-Cw*0602. In parallel, we investigated the epigenetic profile of the critical PSORS1 interval and uncovered three enhancer elements likely to be active in T lymphocytes. Finally we showed that nine candidate susceptibility SNPs map within a HLA-C enhancer and that three of these variants co-localise with binding sites for immune-related transcription factors. These data indicate that SNPs affecting HLA-Cw*0602 expression are likely to contribute to psoriasis susceptibility and highlight the importance of integrating multiple experimental approaches in the investigation of complex genomic regions such as the MHC.


Assuntos
Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença/genética , Antígenos HLA-C/genética , Psoríase/genética , Alelos , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 6/genética , Epigênese Genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Proteínas/genética , RNA Longo não Codificante , Análise de Sequência de DNA , Linfócitos T/metabolismo
17.
Nat Genet ; 45(2): 136-44, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23263490

RESUMO

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , DNA Polimerase III/genética , DNA Polimerase II/genética , Replicação do DNA/genética , Modelos Moleculares , Exodesoxirribonucleases/genética , Ligação Genética , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa/genética , Humanos , Repetições de Microssatélites/genética , Linhagem , Proteínas de Ligação a Poli-ADP-Ribose , Schizosaccharomyces/genética , Análise de Sequência de DNA
18.
Nat Genet ; 44(12): 1341-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23143594

RESUMO

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Imunidade Inata/genética , Psoríase/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/imunologia , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Estudo de Associação Genômica Ampla , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Psoríase/imunologia , Receptores Imunológicos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Pele/imunologia , Linfócitos T/imunologia , População Branca/genética
19.
Nat Genet ; 42(11): 973-7, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20972440

RESUMO

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10⁻¹° and rs6687758, OR = 1.09, P = 2.27 × 10⁻9, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10⁻8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10⁻¹° and rs7136702, OR = 1.06, P = 4.02 × 10⁻8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10⁻¹°). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mapeamento Cromossômico/métodos , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Metanálise como Assunto , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Medição de Risco
20.
Cancer Res ; 69(18): 7422-9, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19723657

RESUMO

Genome-wide association studies have identified several common single nucleotide polymorphisms (SNP) associated with an increased risk of colorectal cancer (CRC), although they have failed to identify any recessively acting alleles that contribute to disease risk. However, two recent studies have suggested that inbreeding and runs of homozygosity (ROH) increase the risk of developing cancer, perhaps by exposing recessive alleles as a result of autozygosity. To examine these results in a relatively large case-control series, we analyzed samples from a cohort in the United Kingdom comprising 921 colorectal tumor cases and 929 controls. Individuals were genotyped using a 550,000 tagging SNP panel. Additionally, we identified from these SNPs a set of approximately 30,000 SNPs in low pairwise linkage disequilibrium. To determine whether homozygosity was associated with CRC, we performed multiple tests to assess homozygosity at individual SNPs and ROHs in cases and controls. No association was found between CRC and (i) homozygosity at any individual SNP, (ii) overall homozygosity or level of inbreeding, (iii) total length or number of ROHs per individual, or (iv) a ROH at any particular genomic location. In conclusion, our results from a large case-control series do not replicate those of previous studies and suggest that homozygosity/autozygosity is not a major risk factor for CRC in an outbred population.


Assuntos
Neoplasias Colorretais/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genoma Humano , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sexo , Reino Unido
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