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1.
Nat Genet ; 44(9): 968-71, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22863734

RESUMO

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Adulto , Criança , Fenda Labial/complicações , Fenda Labial/epidemiologia , Fissura Palatina/complicações , Fissura Palatina/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pais , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco , Síndrome
2.
Exp Dermatol ; 21(5): 390-3, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22509838

RESUMO

Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Alopecia/genética , Variação Genética/genética , Proteínas de Membrana/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Alelos , Alopecia/etnologia , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Alemanha , Humanos , Reino Unido
3.
Int J Pediatr Otorhinolaryngol ; 75(1): 49-52, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21044801

RESUMO

OBJECTIVE: Studies in mice and humans have suggested that SUMO1, which codes for the small ubiquitin-related modifier 1 (SUMO1), is a promising candidate gene for non-syndromic cleft lip with or without cleft palate (NSCL/P). To investigate the possible involvement of this gene in NSCL/P patients from Central Europe, we performed: (i) a case control association study, and (ii) a resequencing study. METHODS: Genotyping and the subsequent single marker and haplotype association analyses were performed for 413 NSCL/P patients and 412 controls. A total of 17 tagging single-nucleotide polymorphisms (SNPs) were used. In the resequencing study, the complete coding region and splice sites were sequenced in 65 index patients from multiply affected families. RESULTS: One of the 17 tested SNPs (rs16838917) had a borderline significant P-value of 0.0416 in the single-marker association analysis. However, this result did not withstand correction for multiple testing (P(corr)=0.707). No association was observed for any haplotypic marker combination. Sequencing failed to identify any novel rare sequence variants. CONCLUSIONS: The results of the present study do not support the hypothesis that common or rare variants in SUMO1 play a significant role in the development of NSCL/P in Central-European patients. However, smaller effects of common variants or the presence of rare high penetrance mutations in other non-investigated familial cases cannot be excluded. Further analysis of SUMO1 in independent samples from Central European and other populations is therefore warranted.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/epidemiologia , Polimorfismo de Nucleotídeo Único , Proteína SUMO-1/genética , Alelos , Estudos de Casos e Controles , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Europa Oriental/epidemiologia , Feminino , Estudos de Associação Genética , Variação Genética , Genótipo , Humanos , Incidência , Masculino , Linhagem
5.
Nat Genet ; 42(1): 24-6, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20023658

RESUMO

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 x 10(-8), relative risk in homozygotes = 1.84, 95% CI 1.34-2.53) and 10q25.3 (rs7078160, combined P = 1.92 x 10(-8), relative risk in homozygotes = 2.17, 95% CI 1.32-3.56).


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Mapeamento Cromossômico , Fenda Labial/complicações , Fissura Palatina/complicações , Humanos , Polimorfismo de Nucleotídeo Único
6.
Am J Hum Genet ; 78(1): 52-62, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16385449

RESUMO

We searched for linkage disequilibrium (LD) in 137 triads with dyslexia, using markers that span the most-replicated dyslexia susceptibility region on 6p21-p22, and found association between the disease and markers within the VMP/DCDC2/KAAG1 locus. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. In a second step, the study was extended to include an independent sample of 239 triads with dyslexia, in which the association--in particular, with the severe phenotype of dyslexia--was confirmed. Our expression data showed that DCDC2, which contains a doublecortin homology domain that is possibly involved in cortical neuron migration, is expressed in the fetal and adult CNS, which--together with the hypothesized protein function--is in accordance with findings in dyslexic patients with abnormal neuronal migration and maturation.


Assuntos
Cromossomos Humanos Par 6/genética , Dislexia/genética , Predisposição Genética para Doença , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Sequência de Bases , Northern Blotting , Sistema Nervoso Central/metabolismo , Primers do DNA , Componentes do Gene , Marcadores Genéticos/genética , Genótipo , Alemanha , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Análise de Sequência de DNA
7.
Genome Res ; 13(10): 2271-6, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14525928

RESUMO

The detailed investigation of variation in functionally important regions of the human genome is expected to promote understanding of genetically complex diseases. We resequenced 65 candidate genes for CNS disorders in an average of 85 European individuals. The minor allele frequency (MAF), an indicator of weak purifying selection, was lowest in radical amino acid alterations, whereas similar MAF was observed for synonymous variants and conservative amino acid alterations. In noncoding sequences, variants located in CpG islands tended to have a lower MAF than those outside CpG islands. The transition/transversion ratio was increased among both synonymous and conservative variants compared with noncoding variants. Conversely, the transition/transversion ratio was lowest among radical amino acid alterations. Furthermore, among nonsynonymous variants, transversions displayed lower MAF than did transitions. This suggests that transversions are associated with functionally important amino acid alterations. By comparing our data with public SNP databases, we found that variants with lower allele frequency are underrepresented in these databases. Therefore, radical variants obtain distinctively lower database coverage. However, those variants appear to be under weak purifying selection and thus could play a role in the etiology of genetically complex diseases.


Assuntos
Doenças do Sistema Nervoso Central/genética , Testes Genéticos , Variação Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Vigilância da População , Alelos , Códon/genética , DNA Intergênico/genética , Bases de Dados Genéticas , Frequência do Gene/genética , Genes/genética , Humanos , Regiões não Traduzidas/genética
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