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1.
Nat Genet ; 49(5): 789-794, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28346443

RESUMO

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.


Assuntos
Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Glioblastoma/genética , Glioma/genética , Alelos , Neoplasias Encefálicas/classificação , Regulação Neoplásica da Expressão Gênica , Genótipo , Glioblastoma/classificação , Glioma/classificação , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
2.
J Am Coll Cardiol ; 69(7): 823-836, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28209224

RESUMO

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.


Assuntos
Doença da Artéria Coronariana/genética , Loci Gênicos , Pleiotropia Genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único
3.
Stroke ; 47(12): 2904-2909, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27827325

RESUMO

BACKGROUND AND PURPOSE: Carotid intima-media thickness is a marker for subclinical atherosclerosis that predicts subsequent clinical cardiovascular events. The aim of this study was to identify chromosomal loci with linkage or association to common carotid intima-media thickness. METHODS: Nuclear families were recruited using the single parental proband sib-pair design. Genotype data were available for 546 individuals from 132 nuclear families of the Bonn IMT Family Study using the Affymetrix GeneChip Human Mapping 250K Sty chip. Multipoint logarithm of the odds (LOD) scores were determined with the quantitative trait locus statistic implemented in multipoint engine for rapid likelihood. Linkage analysis and family-based association tests were conducted. Data from 2471 German participants from the HNR (Heinz Nixdorf Recall) Study were used for subsequent replication. RESULTS: Two new genomic regions with suggestive linkage (LOD>2) were identified on chromosome 4 (LOD=2.26) and on chromosome 17 (LOD=2.01). Previously reported linkage findings were replicated on chromosomes 13 and 14. Fifteen single nucleotide polymorhisms, located on chromosomes 4, 6, and 9, revealed P<10-4 in the family-based association analyses. One of these signals was replicated in HNR (rs2416804, 1-sided P=1.60×10-3, located in the gene TRAF1). CONCLUSIONS: This study presents the first genome-wide linkage and association study of common carotid intima-media thickness in the German population. Alleles of rs2416804 in TRAF1 were identified as being linked and associated with carotid intima-media thickness. Further studies are needed to evaluate the contribution of this locus to the development of atherosclerosis.


Assuntos
Aterosclerose/genética , Espessura Intima-Media Carotídea , Fator 1 Associado a Receptor de TNF/genética , Adulto , Idoso , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Familiar
4.
J Invest Dermatol ; 136(8): 1559-1567, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27060448

RESUMO

Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date, but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPCs) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPCs in hair-related studies often lack dermal papilla characteristics. In contrast, immortalized DPCs have high resemblance to intact dermal papilla. We derived immortalized human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retained high proportions of dermal papilla signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 (twist family basic helix-loop-helix transcription factor 1) and SSPN (sarcospan) to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularization around the hair follicle may contribute to the development of AGA.


Assuntos
Alopecia/genética , Derme/citologia , Regulação da Expressão Gênica , Pele/citologia , Androgênios/metabolismo , Biópsia , Proteínas de Transporte/genética , Linhagem Celular , Núcleo Celular/metabolismo , Análise por Conglomerados , Perfilação da Expressão Gênica , Folículo Piloso/metabolismo , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Receptores Androgênicos/genética , Couro Cabeludo , Proteína 1 Relacionada a Twist/genética , Receptor Xedar
5.
N Engl J Med ; 374(12): 1134-44, 2016 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-26934567

RESUMO

BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).


Assuntos
Angiopoietinas/genética , Moléculas de Adesão Celular/genética , Doença da Artéria Coronariana/genética , Lipase Lipoproteica/genética , Mutação , Triglicerídeos/sangue , Idoso , Proteína 4 Semelhante a Angiopoietina , Feminino , Técnicas de Genotipagem , Humanos , Lipase Lipoproteica/antagonistas & inibidores , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fatores de Risco , Análise de Sequência de DNA , Triglicerídeos/genética
6.
Eur J Hum Genet ; 24(5): 717-24, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26264438

RESUMO

To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.


Assuntos
Neoplasias Encefálicas/genética , Exoma , Loci Gênicos , Técnicas de Genotipagem/métodos , Glioma/genética , Polimorfismo de Nucleotídeo Único , Algoritmos , Aminoacil-tRNA Sintetases/genética , Proteína BRCA2/genética , Estudos de Casos e Controles , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade
7.
Eur J Hum Genet ; 24(6): 895-902, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26508577

RESUMO

The global demand for products that effectively prevent the development of male-pattern baldness (MPB) has drastically increased. However, there is currently no established genetic model for the estimation of MPB risk. We conducted a prediction analysis using single-nucleotide polymorphisms (SNPs) identified from previous GWASs of MPB in a total of 2725 German and Dutch males. A logistic regression model considering the genotypes of 25 SNPs from 12 genomic loci demonstrates that early-onset MPB risk is predictable at an accuracy level of 0.74 when 14 SNPs were included in the model, and measured using the area under the receiver-operating characteristic curves (AUC). Considering age as an additional predictor, the model can predict normal MPB status in middle-aged and elderly individuals at a slightly lower accuracy (AUC 0.69-0.71) when 6-11 SNPs were used. A variance partitioning analysis suggests that 55.8% of early-onset MPB genetic liability can be explained by common autosomal SNPs and 23.3% by X-chromosome SNPs. For normal MPB status in elderly individuals, the proportion of explainable variance is lower (42.4% for autosomal and 9.8% for X-chromosome SNPs). The gap between GWAS findings and the variance partitioning results could be explained by a large body of common DNA variants with small effects that will likely be identified in GWAS of increased sample sizes. Although the accuracy obtained here has not reached a clinically desired level, our model was highly informative for up to 19% of Europeans, thus may assist decision making on early MPB intervention actions and in forensic investigations.


Assuntos
Alopecia/genética , Genótipo , Adulto , Idoso , Estudos de Casos e Controles , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
Nat Commun ; 6: 8559, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26424050

RESUMO

Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10(-11)), 12q21.2 (rs12230172, P=7.53 × 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glioma/genética , Feminino , Genótipo , Glioma/classificação , Humanos , Masculino , Pessoa de Meia-Idade
10.
PLoS Genet ; 11(3): e1005024, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25763902

RESUMO

The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.


Assuntos
Extrofia Vesical/genética , Estudo de Associação Genômica Ampla , Proteínas com Homeodomínio LIM/genética , Fatores de Transcrição/genética , Animais , Estudos de Casos e Controles , Humanos , Proteínas com Homeodomínio LIM/metabolismo , Camundongos , Fatores de Transcrição/metabolismo
11.
Neurobiol Aging ; 36(3): 1605.e13-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25659857

RESUMO

We studied the association of SORL1 single-nucleotide polymorphisms genotypes with measures of pathology in patients with probable Alzheimer's disease (AD) using an endophenotype approach. We included (1) 133 patients from the German Dementia Competence Network (71 ± 8 years; 50% females; Mini Mental State Examination [MMSE], 24 ± 3); (2) 83 patients from the Alzheimer's Disease Neuroimaging Initiative (75 ± 8 years; 45% females; MMSE, 24 ± 2); and (3) 452 patients from the Amsterdam Dementia Cohort 66 ± 8 years; 47% females; MMSE, 20 ± 5). As endophenotype markers we used cognitive tests, cerebrospinal fluid (CSF) biomarkers amyloid-beta, total tau (tau), tau phosphorylated at threonine 181, and hippocampal atrophy. We measured 19 SORL1 SNP alleles. Genotype-endophenotype associations were determined by linear regression analyses. There was an association between rs2070045-G allele and increased CSF-tau and more hippocampal atrophy. Additionally, haplotype-based analyses revealed an association between haplotype rs11218340-A/rs3824966-G/rs3824968-A and higher CSF-tau and CSF-tau phosphorylated at threonine 181. In conclusion, we found that SORL1 SNP rs2070045-G allele was related to CSF-tau and hippocampal atrophy, 2 endophenotype markers of AD, suggesting that SORL1 may be implicated in the downstream pathology in AD.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Amidas , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Fosfóricos , Proteínas tau/líquido cefalorraquidiano
12.
Nat Commun ; 6: 5966, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25608926

RESUMO

Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.


Assuntos
Alopecia em Áreas/genética , Proteínas Reguladoras de Apoptose/genética , Ataxina-2/genética , Predisposição Genética para Doença , Antígenos HLA/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Animais , Proteína 11 Semelhante a Bcl-2 , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Microscopia de Fluorescência , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Análise de Componente Principal , Conformação Proteica , Pele/metabolismo
14.
Int J Cancer ; 136(6): E578-89, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25219767

RESUMO

To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (ß-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant.


Assuntos
Polipose Adenomatosa do Colo/genética , Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Adulto , Idoso , Criança , DNA Glicosilases/genética , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP110/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinesina/genética , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , beta Catenina/genética
15.
Nat Genet ; 46(8): 901-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997987

RESUMO

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQß1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQß1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.


Assuntos
Acalasia Esofágica/genética , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Alelos , Substituição de Aminoácidos , Estudos de Casos e Controles , Acalasia Esofágica/imunologia , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Antígenos HLA-DQ/química , Haplótipos , Humanos , Modelos Logísticos , Masculino , Modelos Moleculares , Polimorfismo de Nucleotídeo Único
16.
Hum Mol Genet ; 23(24): 6644-58, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25027320

RESUMO

Cerebrospinal fluid amyloid-beta 1-42 (Aß1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aß1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aß1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aß1-42.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Apolipoproteína E4/genética , Proteínas Nucleares/genética , Fragmentos de Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Proteínas tau/genética , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/líquido cefalorraquidiano , Cognição , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas Nucleares/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Proteínas de Ligação a RNA/líquido cefalorraquidiano , Fatores de Processamento de Serina-Arginina , Transdução de Sinais , Proteínas tau/líquido cefalorraquidiano
17.
Neurobiol Aging ; 35(11): 2657.e13-2657.e19, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25042114

RESUMO

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.


Assuntos
Demência Frontotemporal/genética , Estudos de Associação Genética , Variação Genética/genética , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Feminino , Demência Frontotemporal/classificação , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA
18.
Bipolar Disord ; 16(7): 764-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24754353

RESUMO

OBJECTIVES: Copy number variants (CNVs) have been shown to affect susceptibility for neuropsychiatric disorders. To date, studies implicating the serotonergic system in complex conditions have just focused on single nucleotide polymorphisms (SNPs). We therefore sought to identify novel common genetic copy number polymorphisms affecting genes of the serotonergic system, and to assess their putative role in bipolar affective disorder (BPAD) and major depressive disorder (MDD). METHODS: A selection of 41 genes of the serotonergic system encoding receptors, the serotonin transporter, metabolic enzymes and chaperones were investigated using a paired-end mapping (PEM) approach on next-generation sequencing data from the pilot project of the 1000 Genomes Project. For association testing, 593 patients with MDD, 1,145 patients with BPAD, and 1,738 healthy controls were included in the study. RESULTS: PEM led to the identification of a microdeletion in the gene encoding tryptophan hydroxylase 2 (TPH2), affecting an amygdala- and hippocampus-specific isoform. It was not associated with BPAD or MDD using a case-control association approach. CONCLUSIONS: We did not find evidence for a role of the TPH2 microdeletion in the pathoetiology of affective disorders. Further studies examining its putative role in behavioral traits regulated by the limbic system are warranted.


Assuntos
Tonsila do Cerebelo/patologia , Predisposição Genética para Doença/genética , Hipocampo/patologia , Transtornos do Humor/genética , Transtornos do Humor/patologia , Polimorfismo de Nucleotídeo Único/genética , Triptofano Hidroxilase/genética , Feminino , Humanos , Desequilíbrio de Ligação , Masculino
19.
Arch Dermatol Res ; 306(4): 413-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24352509

RESUMO

Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL.


Assuntos
Alopecia/genética , Receptores Androgênicos/genética , Proteínas Wnt/genética , Receptor Xedar/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Via de Sinalização Wnt/genética
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