RESUMO
Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.
Assuntos
Cromossomos Humanos Par 3 , GTP Fosfo-Hidrolases/genética , Mutação , Atrofia Óptica/genética , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Análise Mutacional de DNA , Drosophila , Dinaminas , Éxons , Feminino , GTP Fosfo-Hidrolases/química , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Linhagem , Saccharomyces cerevisiae/genética , Salmão , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Idoso , Mapeamento Cromossômico , Europa (Continente)/epidemiologia , Europa (Continente)/etnologia , Éxons/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Razão de Chances , Locos de Características QuantitativasRESUMO
A recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in approximately 30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1l and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Biologia Computacional , Proteínas de Ligação a DNA/genética , Saúde da Família , Feminino , Expressão Gênica/genética , Frequência do Gene , Genótipo , Humanos , Irlanda/epidemiologia , Modelos Logísticos , Masculino , Óxido Nítrico Sintase Tipo I/genética , Mudanças Depois da Morte , Esquizofrenia/patologia , Fatores SexuaisRESUMO
The dystrobrevin-binding protein 1 (DTNBP1) gene has been one of the most studied and promising schizophrenia susceptibility genes since it was first reported to be associated with schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF). Although many studies have been performed both at the functional level and in association with psychiatric disorders, there has been no systematic review of the features of the DTNBP1 gene, protein or the relationship between function and phenotype. Using a bioinformatics approach, we identified the DTNBP1 gene in 13 vertebrate species. The comparison of these genes revealed a conserved gene structure, protein-coding sequence and dysbindin domain, but a diverse noncoding sequence. The molecular evolutionary analysis suggests the DTNBP1 gene probably originated in chordates and matured in vertebrates. No signature of recent positive selection was seen in any primate lineage. The DTNBP1 gene likely has many more alternative transcripts than the current three major isoforms annotated in the NCBI database. Our examination of risk haplotypes revealed that, although the frequency of a single nucleotide polymorphism (SNP) or haplotype might be significantly different in cases from controls, difference between major geographic populations was even larger. Finally, we constructed the first DTNBP1 interactome and explored its network features. Besides the biogenesis of lysosome-related organelles complex 1 and dystrophin-associated protein complex, several molecules in the DTNBP1 network likely provide insight into the role of DTNBP1 in biological systems: retinoic acid, beta-estradiol, calmodulin and tumour necrosis factor. Studies of these subnetworks and pathways may provide opportunities to deepen our understanding of the mechanisms of action of DTNBP1 variants.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Evolução Molecular , Polimorfismo de Nucleotídeo Único/genética , Animais , Disbindina , Proteínas Associadas à Distrofina , HumanosRESUMO
Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population.
Assuntos
Cromossomos Humanos Par 10 , Estudo de Associação Genômica Ampla , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Feminino , Ligação Genética , Haplótipos , Humanos , Irlanda , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
SNAP25 occurs on chromosome 20p12.2, which has been linked to schizophrenia in some samples, and recently linked to latent classes of psychotic illness in our sample. SNAP25 is crucial to synaptic functioning, may be involved in axonal growth and dendritic sprouting, and its expression may be decreased in schizophrenia. We genotyped 18 haplotype-tagging SNPs in SNAP25 in a sample of 270 Irish high-density families. Single marker and haplotype analyses were performed in FBAT and PDT. We adjusted for multiple testing by computing q values. Association was followed up in an independent sample of 657 cases and 411 controls. We tested for allelic effects on the clinical phenotype by using the method of sequential addition and 5 factor-derived scores of the OPCRIT. Nine of 18 SNPs had P values <0.05 in either FBAT or PDT for one or more definitions of illness. Several two-marker haplotypes were also associated. Subjects inheriting the risk alleles of the most significantly associated two-marker haplotype were likely to have higher levels of hallucinations and delusions. The most significantly associated marker, rs6039820, was observed to perturb 12 transcription-factor binding sites in in silico analyses. An attempt to replicate association findings in the case-control sample resulted in no SNPs being significantly associated. We observed robust association in both single marker and haplotype-based analyses between SNAP25 and schizophrenia in an Irish family sample. Although we failed to replicate this in an independent sample, this gene should be further tested in other samples.
Assuntos
Esquizofrenia/genética , Proteína 25 Associada a Sinaptossoma/genética , Alelos , Axônios , Estudos de Casos e Controles , Dendritos/patologia , Saúde da Família , Marcadores Genéticos , Haplótipos , Humanos , Irlanda , Modelos Genéticos , Fenótipo , Polimorfismo GenéticoRESUMO
Mutations in the RP2 gene located on Xp11.23 are associated with X-linked retinitis pigmentosa (XLRP), a severe form of progressive retinal degeneration which leads to complete loss of vision in affected males. To date, 14 different mutations in the RP2 gene have been reported to cause XLRP, the majority of which lead to a coding frameshift within the gene and predicted truncation of the protein product. We here report two novel frameshift mutations in RP2 identified in XLRP families by PCR-SSCP and direct sequencing, namely 723delT and 796-799del. Four single nucleotide polymorphisms (SNPs) within the coding region of RP2 are also described (105A>T, 597T>C, 844C>T, 1012G>T), the first polymorphisms to be reported within this gene of unknown function, two of which alter the amino acid sequence. The current study extends the XLRP mutation profile of RP2 and highlights non-pathogenic coding sequence variations which may facilitate both functional studies of the gene and analysis of intragenic allelic contribution to the phenotype.
Assuntos
Proteínas do Olho , Mutação da Fase de Leitura/genética , Variação Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Processamento Alternativo/genética , Proteínas de Ligação ao GTP , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
In our study of sequence variation within the RPGR gene associated with X-linked retinitis pigmentosa, we and others have observed a high rate of new mutation within this gene, as all reported mutations are unique or uncommon. In this article we report the identification in a single family of a complex allele of 7 sequence variants in linkage disequilibrium, of which four result in amino-acid alterations (Arg425Lys, DGlu, Thr533Met and Gly566Glu). This complex allele was initially found in a family with XLRP. However, further study revealed an estimated prevalence of 4.3% (15/344 chromosomes) with this complex allele in the European population indicating the non-pathogenic nature of this allele and, along with previously reported polymorphisms, further supporting a high level of human protein diversity for RPGR. This common complex allele may have been established in the population as a founder effect. Complete gene sequencing identified a potential pathogenic sequence variant in the family described (IVS6+5G>A). This study emphasises the need to create a more complete picture of the allelic variation within a gene, suggests cautious interpretation of a phenotypic association with variant sequences, and highlights the potential problems associated with interpreting genetic studies for diagnostic purposes.
Assuntos
Alelos , Proteínas de Transporte/genética , Proteínas do Olho , Efeito Fundador , Variação Genética/genética , Retinose Pigmentar/genética , Substituição de Aminoácidos/genética , Sequência de Bases , Feminino , Humanos , Masculino , LinhagemRESUMO
PURPOSE: To evaluate the role of TIMP-1 in inherited retinal degeneration. METHODS: The genomic structure of the TIMP-1 gene was established and male patients with x-linked retinitis pigmentosa 2 from five families were screened for sequence alterations by direct sequencing in all exons, exon-intron boundaries, and the 5' upstream region of the gene. RESULTS: TIMP-1 appears to be expressed in the retina at low levels and consists of six exons spanning a genomic region of approximately 4.5 kb on Xp11.23. No disease-specific sequence alterations were identified. A site substitution in exon 5 was observed in samples from control subjects and patients, but it did not alter the amino acid sequence of the protein product. CONCLUSIONS: The results of this study exclude mutations in the TIMP-1 coding sequence, splice sites, and the 5' upstream region as a cause of retinal degeneration in x-linked retinitis pigmentosa 2. However, an as yet unidentified regulatory element that lies outside these intervals may be implicated. The role of this tightly regulated protein in the normal functioning of the retina has yet to be determined.
Assuntos
Ligação Genética , Glicoproteínas/genética , Inibidores de Proteases , Retinose Pigmentar/enzimologia , Cromossomo X/enzimologia , Sequência de Bases , DNA/análise , Análise Mutacional de DNA , Primers do DNA/química , Éxons , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Retina/enzimologia , Retinose Pigmentar/etiologia , Inibidores Teciduais de MetaloproteinasesRESUMO
PURPOSE: X-linked retinitis pigmentosa (XLRP) is a degenerative disease of the retina characterized in the early stages of disease by night blindness as a result of rod photoreceptor loss, progressing to severe disease with loss of central vision by the third decade in affected males. XLRP displays exceptional genetic heterogeneity, with five reported loci on the human X-chromosome. To investigate the level of heterogeneity for XLRP in the patient pool in the current study, extensive haplotype analysis, linkage analysis, and mutation screening were performed. METHODS: Haplotype analysis of a family with diagnosed XLRP was scored with more than 34 polymorphic markers spanning the entire X-chromosome, including regions already identified as harboring XLRP genes and retina-specific genes. Two-point and multipoint lod scores were calculated. Affected male DNA was amplified with primers specific for the retinoschisis gene (XLRS1), and the products were screened for nucleic acid alterations by direct automated sequencing. RESULTS: In this article haplotype and linkage data are presented identifying a new locus for XLRP on the short arm of the X-chromosome, distinct from previously reported gene localizations for XLRP. The phenotype is atypical, in that the onset of vision loss in the male members of this family is unusually early, and female obligate carriers have normal fundi and waveforms. Informative recombination events in this family define a locus for XLRP (RP23) on Xp22 between the markers DXS1223 and DXS7161, spanning approximately 15 cM. A maximum lod score of 2.1 was calculated for the locus order DXS7103-8 cM-(RP23/DXS1224)-4 cM-DXS999. This new locus (RP23) encompasses the retinoschisis disease gene; therefore, XLRS1 was screened for a mutation. No sequence alteration was identified indicating that mutations in the coding region of the gene responsible for retinoschisis do not cause RP23. CONCLUSIONS: The results describe evidence for a new locus for XLRP (RP23), adding to the established genetic heterogeneity for this disease and the number of genes expressed in ocular tissue residing on the X-chromosome.
Assuntos
Mapeamento Cromossômico , Ligação Genética , Retinose Pigmentar/genética , Cromossomo X , Adulto , Portador Sadio , Criança , Análise Mutacional de DNA , Feminino , Heterogeneidade Genética , Haplótipos , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Retinose Pigmentar/patologiaRESUMO
BACKGROUND/AIMS: Patients with autosomal dominant optic atrophy (ADOA) are genetically heterogeneous, but all have disc pallor. A degree of cupping in ADOA can make the distinction from normal tension glaucoma (NTG) clinically difficult. This study aimed to clarify the features of the optic nerve of patients with ADOA at the OPA1 locus. METHODS: 29 patients (58 eyes), from 12 families, were identified in a prospective observational study of patients with ADOA examined by a single observer between 1995 and 1998, in whom genetic analysis showed either evidence for linkage to chromosome 3q28 or mutations in the ADOA gene, OPA1. All of the patients had disc and fundal photographs available for retrospective analysis. Clinical data collected included disc appearance, intraocular pressure, Snellen visual acuity, Hardy-Rand-Rittler colour vision plates, and Humphrey 30-2 visual fields. RESULTS: Mean age at time of examination was 37 years and mean visual acuity was 6/24. Disc morphology showed temporal disc pallor in 30 eyes (52%) and total disc pallor in 28 eyes (48%). At least one disc showed a cup to disc ratio of more than 0.5 in 18 patients (28 discs, 48%). The temporal neuroretinal rim always showed pallor and shallow shelving (or saucerisation) was seen in 46 eyes (79%). Only 12 discs (21%) had deep excavation and baring of blood vessels. All of the patients had normal intraocular pressure and no family history of glaucoma. There was a temporal grey, pigmentary crescent in 12 patients (18 eyes, 31%) and peripapillary atrophy in 20 patients (40 eyes, 69%), but disc margin haemorrhages were not seen. There was no maculopathy or retinopathy. CONCLUSION: The optic disc morphology, described for the first time in this genetically homogeneous population of patients with OPA1 ADOA, shows a distinctive absence of a healthy neuroretinal rim and shallow saucerisation of the optic disc cup, with frequent peripapillary atrophy.
Assuntos
GTP Fosfo-Hidrolases/genética , Atrofia Óptica Autossômica Dominante/patologia , Disco Óptico/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 3/genética , Feminino , Ligação Genética/genética , Genótipo , Humanos , Masculino , Mutação/genética , Atrofia Óptica Autossômica Dominante/genética , Linhagem , Fenótipo , Fotografação , Estudos ProspectivosRESUMO
AIM: X linked retinitis pigmentosa (XLRP) has two genetic loci known as "RP2" and "RP3". Clinical features reported to differentiate RP2 from RP3 include a higher prevalence of myopia and primary cone dysfunction in RP2, and late onset night blindness and tapetal reflex in RP3. Members from 14 XLRP families were examined in an attempt to verify these differences. METHODS: 16 affected males and 37 females from 14 XLRP families assigned as either RP2 or RP3 by haplotype analysis and/or by heterogeneity analysis were examined. Members of all 14 families who were willing to participate but unavailable for examination were contacted and detailed interviews carried out. RESULTS: No clear phenotypic differences were found that could be used to reliably differentiate RP2 from RP3 with respect to myopia and onset of night blindness. The tapetal reflex was also found to be present in carriers of both RP2 and RP3. CONCLUSIONS: XLRP is a heterogeneous class of rod degenerative disorders with no clear phenotypic differentiation between the two genetic loci RP2 and RP3. There is a continuum of clinical presentations which can be seen in both RP2 and RP3, but the features within a given family tend to be consistent. However, interfamilial variability is prevalent leading to a wide range of clinical presentations and more than one abnormal allele at each gene locus cannot be excluded.
Assuntos
Proteínas do Olho , Ligação Genética , Proteínas/genética , Retinose Pigmentar/genética , Cromossomo X , Adulto , Idoso , Feminino , Fundo de Olho , Proteínas de Ligação ao GTP , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Miopia/etiologia , Cegueira Noturna/etiologia , Fenótipo , Retinose Pigmentar/complicaçõesRESUMO
Autism and schizophrenia are highly heritable neurodevelopmental disorders, each mediated by a diverse suite of genetic and environmental risk factors. Comorbidity and familial aggregation of such neurodevelopmental disorders with other disease-related conditions can provide important insights into their etiology. Epidemiological studies have documented reduced rates of rheumatoid arthritis, a systemic autoimmune condition, in schizophrenia, and recent work has shown increased rates of rheumatoid arthritis in first-degree relatives of autistic individuals, especially mothers. Advances in understanding the genetic basis of rheumatoid arthritis have shown that much of the genetic liability to this condition is due to risk and protective alleles at the HLA DRB1 locus. These data allow robust testing of the hypotheses that allelic variation at DRB1 pleiotropically modulates risk of rheumatoid arthritis, autism and schizophrenia. Systematic review of the literature indicates that reported associations of DRB1 variants with these three conditions are congruent with a pleiotropic model: DRB1*04 alleles have been associated with increased risk of rheumatoid arthritis and autism but decreased risk of schizophrenia, and DRB1*13 alleles have been associated with protection from rheumatoid arthritis and autism but higher risk of schizophrenia. These convergent findings from genetics and epidemiology imply that a subset of autism and schizophrenia cases may be underlain by genetically based neuroimmune alterations, and that analyses of the causes of risk and protective effects from DRB1 variants may provide new approaches to therapy.
Assuntos
Artrite Reumatoide/imunologia , Transtorno Autístico/imunologia , Cadeias HLA-DRB1/genética , Fenômenos Imunogenéticos , Esquizofrenia/imunologia , Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Transtorno Autístico/complicações , Transtorno Autístico/genética , Autoimunidade/genética , Autoimunidade/imunologia , Feminino , Variação Genética , Cadeias HLA-DRB1/imunologia , Humanos , Masculino , Neuroimunomodulação/genética , Neuroimunomodulação/imunologia , Esquizofrenia/complicações , Esquizofrenia/genéticaRESUMO
The TAAR6 gene has been previously associated with schizophrenia in 192 pedigrees of European and African ancestry. To replicate these findings we performed an association study of TAAR6 in 265 pedigrees of the Irish Study of High-Density Schizophrenia Families (ISHDSF). Of the 24 genotyped single-nucleotide polymorphisms only rs12189813 and rs9389011 provided single-marker evidence for association (0.0094Assuntos
Proteínas de Ciclo Celular/genética
, Saúde da Família
, Ligação Genética
, Proteínas Nucleares/genética
, Polimorfismo de Nucleotídeo Único
, Esquizofrenia/genética
, Biologia Computacional/métodos
, Feminino
, Frequência do Gene
, Predisposição Genética para Doença
, Humanos
, Irlanda/epidemiologia
, Masculino
, Modelos Moleculares
, Peso Molecular
, Receptores Acoplados a Proteínas G
, Esquizofrenia/fisiopatologia
RESUMO
We investigated the association of the NRG1 gene and schizophrenia using meta-analytic techniques, combining all published data while restricting our analysis to studies investigating the most commonly reported single marker (SNP8NRG221533). We also investigated whether ancestry (European vs East Asian) and study design (family-based vs case-control) moderated any association. We found no evidence for an association of SNP8NRG221533 with schizophrenia, and significant between-study heterogeneity, which persisted when family-based studies were combined separately. However, when haplotype-based P-values were combined, there was evidence in support of an association of NRG1 with schizophrenia, and no evidence of between-study heterogeneity. Our meta-analysis provides support for the association of NRG1 with schizophrenia, but indicates that firmly establishing the role of NRG1 gene in schizophrenia by genetic association requires much larger sample sizes than have hitherto been reported. Association analyses and replications should take place at the level of the gene, rather than at the level of SNP, haplotype, or functional variant. Meta-analysis would then be carried out on the basis of the combination of P-values.
Assuntos
Haplótipos/genética , Neuregulina-1/genética , Esquizofrenia/genética , Povo Asiático/genética , Ásia Oriental , Marcadores Genéticos/genética , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra , População Branca/genéticaRESUMO
Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003Assuntos
Transtornos Relacionados ao Uso de Álcool/genética
, Proteínas de Transporte/genética
, Cromossomos Humanos Par 19/genética
, Fatores de Transcrição/genética
, Dedos de Zinco/genética
, Animais
, Estudos de Casos e Controles
, Proteínas de Drosophila/genética
, Predisposição Genética para Doença/genética
, Haplótipos
, Humanos
, Desequilíbrio de Ligação
, Polimorfismo de Nucleotídeo Único
, Valores de Referência
, Irmãos
RESUMO
Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50-60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 x 10(-6), at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0-2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.
Assuntos
Transtornos Relacionados ao Uso de Álcool/genética , Cromossomos Humanos Par 4/genética , Predisposição Genética para Doença , Idoso , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Irmãos , Estatísticas não ParamétricasRESUMO
Twenty-two X-linked cosmid clones have been localised by fluorescence in situ hybridisation (FISH). Twelve map to the long arm of the X chromosome and 10 to the short arm. Seven of the latter cosmids and an additional one were mapped by two colour FISH relative to reference markers DXS7 and DXS426 in proximal Xp. Finer localisation of one of the cosmids, namely HX43 was achieved by isolation of a microsatellite followed by genetic mapping with respect to reference markers in the region.
Assuntos
Cosmídeos/química , DNA Satélite/análise , Retinose Pigmentar/genética , Cromossomo X/ultraestrutura , Sequência de Bases , Ligação Genética , Humanos , Hibridização in Situ Fluorescente , Escore Lod , Dados de Sequência MolecularRESUMO
Five polymorphic CA-dinucleotide repeats, identified in cosmids from the short arm of the human X chromosome, have been characterized and localized to Xp21.1 (DXS572), Xp11.4 (DXS556, DXS574), and Xp11.22-p11.23 (DXS722, DXS573). Genetic mapping with respect to five reference markers that include the gene for CGD (CYBB in Xp21.1), complemented by physical mapping information, has indicated the order tel-DXS572-CYBB-DXS1110-DXS556-DXS574-D XS7-DXS426-DXS722-DXS573-DXS255-cen.
Assuntos
DNA Satélite/genética , Hominidae/genética , Sequências Repetitivas de Ácido Nucleico , Cromossomo X , Animais , Sequência de Bases , Deleção Cromossômica , Mapeamento Cromossômico , Primers do DNA , Triagem de Portadores Genéticos , Marcadores Genéticos , Humanos , Células Híbridas , Meiose , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Recombinação GenéticaRESUMO
Three microsatellites have been identified in cosmids from the human X chromosome. The cosmids have been assigned locus numbers DXS554, DXS559, and DXS566 and have been localized to Xq12-q13 (DXS554 and DXS559) and Xq13 (DXS566). In addition, they have been genetically mapped in relation to the androgen receptor (AR), phosphoglycerate kinase 1, pseudogene 1 (PGK1P1), and phosphoglycerate kinase (PGK1) loci in the proximal long arm. Genetically, the localization of microsatellites at DXS554 and DXS566 is indistinguishable from PGK1, whereas that at DXS559 maps between AR and PGK1, close to PGK1P1. DXS566 is identical to the independently identified DXS441 marker. These markers should be useful for physical and genetic mapping in this region.