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1.
Mol Psychiatry ; 17(4): 433-44, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21423239

RESUMO

The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Tentativa de Suicídio/psicologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo
2.
Mol Psychiatry ; 16(2): 193-201, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20125088

RESUMO

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Mapeamento Cromossômico , Europa (Continente) , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Recidiva , Fatores Sexuais , Fator de Transcrição Sp4/genética
3.
Am J Med Genet B Neuropsychiatr Genet ; 153B(2): 549-553, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-19691043

RESUMO

The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female) = 1.79, P = 8.9 x 10(-5) vs. OR(Male) = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support.


Assuntos
Transtorno Bipolar/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/genética , Alelos , Saúde da Família , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Modelos Genéticos , Neurônios/metabolismo , Controle de Qualidade , Fatores de Risco , Esquizofrenia/genética , Fatores Sexuais
4.
Mol Psychiatry ; 14(3): 261-8, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18180755

RESUMO

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Proteínas de Ligação a Tacrolimo/genética , Transtorno Bipolar/fisiopatologia , Estudos de Coortes , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Desequilíbrio de Ligação , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , Linhagem , Sistema Hipófise-Suprarrenal/fisiopatologia , Polimorfismo de Nucleotídeo Único
5.
Mol Psychiatry ; 12(7): 630-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17505464

RESUMO

Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a non-parametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Ligação Genética , Predisposição Genética para Doença/genética , Idade de Início , Transtorno Bipolar/classificação , Mapeamento Cromossômico , Humanos , Transtornos do Humor/classificação , Transtornos do Humor/genética , Linhagem , Estatísticas não Paramétricas
6.
Genet Epidemiol ; 30(2): 155-69, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16385469

RESUMO

By adapting a well-known affected-relative-pair linkage model that can incorporate covariate or sub-phenotype information [Olson, 1999: Am J Hum Genet 65:1760-1769], we have developed a recursive-partitioning (RP) algorithm (tree-based model) for identifying phenotype and covariate groupings that interact with the evidence for linkage. This strategy is designed to identify subgroups of affected relative pairs demonstrating increased evidence for linkage, where subgroups are defined by pair-level or family-level covariates. After growing a full tree, we identified optimal tree size through a form of tree pruning and chose the best covariate at each split by using bootstrap algorithms. Simulation studies showed that power to detect linkage can increase in the presence of gene-environment interactions, depending on the magnitude of the interaction. As expected, however, power can decrease by examining more covariates, despite the pruning to optimize tree size. The RP model correctly identifies tree structure in a large proportion of simulations. We applied the RP model to a dataset of families with bipolar affective disorder (BPAD) where linkage regions on chromosome 18 have been previously identified. Using the all-pairs score in Genehunter, the NPL tests showed no regions with strong linkage evidence on chromosome 18. However, using the RP model, several suggestive regions were found on chromosome 18. Two covariates appeared to influence the degree of linkage: the type II BPAD subtype and a pattern of displaying mania before or after a depressive episode. The RP model has the potential to identify previously unknown gene-environmental interactions; here we have demonstrated the practical utility and potential this new methodology holds.


Assuntos
Algoritmos , Alelos , Transtorno Bipolar/genética , Ligação Genética , Modelos Genéticos , Cromossomos Humanos Par 18/genética , Humanos , Modelos Estatísticos , Fenótipo
7.
Mol Psychiatry ; 9(2): 191-6, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14966477

RESUMO

Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease-common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 8 , Ligação Genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Adenilil Ciclases/genética , Seguimentos , Predisposição Genética para Doença , Humanos , Canal de Potássio KCNQ3 , Repetições de Microssatélites , Canais de Potássio/genética , Tireoglobulina/genética
8.
Am J Med Genet B Neuropsychiatr Genet ; 124B(1): 15-9, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14681907

RESUMO

The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia.


Assuntos
Transtorno Bipolar/genética , Mutação , Esquizofrenia/genética , Expansão das Repetições de Trinucleotídeos/genética , Genótipo , Humanos , Fatores de Risco
9.
Mol Psychiatry ; 9(1): 87-92; image 5, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14699445

RESUMO

Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 13 , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único
10.
Mol Psychiatry ; 7(6): 579-93, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12140781

RESUMO

Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3'. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.


Assuntos
Transtorno Bipolar/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Distribuição de Qui-Quadrado , Família , Haplótipos , Humanos , Iowa , Maryland , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Psychiatr Genet ; 12(1): 43-7, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11901359

RESUMO

A strong genetic association between the NOTCH4 locus on chromosome 6 and schizophrenia was recently reported. Based on the data suggesting overlapping susceptibility for schizophrenia and bipolar disorder, we genotyped the polymorphic (CTG)n encoding polyleucine repeat in exon 1 of NOTCH4 in 65 pedigrees ascertained for a genetic linkage study of bipolar disorder. In addition, we analyzed a subset of our pedigrees with psychotic features at this locus. We failed to find any association between the (CTG)n NOTCH4 polymorphism and either the bipolar or the psychotic bipolar phenotype in our 65 pedigrees.


Assuntos
Transtorno Bipolar/genética , Polimorfismo Genético , Proteínas Proto-Oncogênicas/genética , Receptores de Superfície Celular , Repetições de Trinucleotídeos/genética , Sequência de Bases , Genótipo , Humanos , Complexo Principal de Histocompatibilidade , Peptídeos , Receptor Notch4 , Receptores Notch
12.
Arch Gen Psychiatry ; 58(11): 1025-31, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11695948

RESUMO

BACKGROUND: An analysis of the relationship between clinical features and allele sharing could clarify the issue of genetic linkage between bipolar affective disorder (BPAD) and chromosome 18q, contributing to the definition of genetically valid clinical subtypes. METHODS: Relatives ascertained through a proband who had bipolar I disorder (BPI) were interviewed by a psychiatrist, assigned an all-sources diagnosis, and genotyped with 32 markers on 18q21-23. Exploratory findings from the first 28 families (n = 247) were tested prospectively in an additional 30 families (n = 259), and the effect of confirmed findings on the linkage evidence was assessed. RESULTS: In exploratory analyses, paternal allele sharing on 18q21 was significantly (P =.03) associated with a diagnostic subtype, and was greatest in pairs where both siblings had bipolar II disorder (BPII). Prospective analysis confirmed the finding that BPII-BPII sibling pairs showed significantly (P =.016) greater paternal allele sharing. Paternal allele sharing across 18q21-23 was also significantly greater in families with at least one BPII-BPII sibling pair. In these families, multipoint affected sibling-pair linkage analysis produced a peak paternal lod score of 4.67 (1-lod confidence interval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence interval, 44 cM) in all families. CONCLUSIONS: Affected sibling pairs with BPII discriminated between families who showed evidence of linkage to 18q, and families who did not. Families with a BPII sibling pair produced an increased lod score and improved linkage resolution. These findings, limited by the small number of BPII-BPII sibling pairs, strengthen the evidence of genetic linkage between BPAD and chromosome 18q, and provide preliminary support for BPII as a genetically valid subtype of BPAD.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 18/genética , Ligação Genética , Idade de Início , Alelos , Transtorno Bipolar/epidemiologia , Feminino , Marcadores Genéticos , Haplótipos/genética , Humanos , Masculino , Linhagem , Estudos Prospectivos , Reprodutibilidade dos Testes , Distribuição por Sexo
13.
Am J Psychiatry ; 158(8): 1258-64, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11481160

RESUMO

OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Delusões/diagnóstico , Delusões/genética , Família , Alucinações/diagnóstico , Alucinações/genética , Adulto , Transtornos Psicóticos Afetivos/diagnóstico , Transtornos Psicóticos Afetivos/epidemiologia , Transtornos Psicóticos Afetivos/genética , Biomarcadores , Transtorno Bipolar/epidemiologia , Análise por Conglomerados , Comorbidade , Delusões/epidemiologia , Feminino , Predisposição Genética para Doença , Alucinações/epidemiologia , Humanos , Masculino , Linhagem , Fenótipo , Índice de Gravidade de Doença
14.
Eur J Hum Genet ; 9(12): 922-30, 2001 12.
Artigo em Inglês | MEDLINE | ID: mdl-11840194

RESUMO

The validation of full-length cDNA represents a crucial step in gene identification and subsequent functional analysis. In searching for candidate genes for bipolar disorder on chromosome 18q21, a novel gene homologous to NEDD4 (Neural precursor cells expressed developmentally down-regulated) was identified using exon trapping and cDNA cloning. This novel gene is termed NEDD4L (Human Gene Nomenclature Committee symbol). Typical NEDD4 orthologues that contain a C2 (Ca(2+)/lipid-binding) and a HECT (Homologous to the E6-AP Carboxyl Terminus) ubiquitin-protein ligase domain, and multiple WW domains have been shown to regulate the epithelial sodium channel (ENaC). In mice, Nedd4 has two distinct isoforms termed Nedd4-1 that belongs to the typical NEDD4 class, and Nedd4-2 that is homologous to Nedd4-1 but lacks the C2 domain. NEDD4L contains the WW and HECT domains seen in the NEDD4 gene family, but lacks the C2 domain in the N-terminus. BLAST database search showed that the deduced polypeptide of NEDD4L has 97 and 62% sequence identity to mouse Nedd4-2 and human NEDD4, respectively. Multiple forms of transcripts of NEDD4L have been isolated, which differ in transcription start and termination sites together with the presence or absence of an alternative spliced exon. Northern blot analysis showed a 3.4 kb mRNA species was specifically expressed in heart and skeletal muscle, while a 3.2 kb band and/or an additional 3.6 kb band is seen in other tissues tested. Striking homology of NEDD4L to mouse Nedd4-2 suggests it is the human homologue of mouse Nedd4-2. Its position in a region of linkage for autosomal dominant orthostatic hypotensive disorder and its potential role in regulating ENaC make NEDD4L a candidate gene for this disorder.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos Par 18/genética , Ligases/genética , Ubiquitina-Proteína Ligases , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Transtorno Bipolar/genética , Mapeamento Cromossômico , Clonagem Molecular , Complexos Endossomais de Distribuição Requeridos para Transporte , Humanos , Hipotensão Ortostática/genética , Camundongos , Dados de Sequência Molecular , Mutação , Ubiquitina-Proteína Ligases Nedd4 , RNA Mensageiro/genética , Análise de Sequência de DNA , Homologia de Sequência
15.
Am J Psychiatry ; 157(12): 2048-50, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11097977

RESUMO

OBJECTIVE: This study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder. METHOD: In 71 families ascertained for a genetic linkage study, 337 subjects with major affective disorder were assessed by using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. RESULTS: Subjects with bipolar disorder and alcoholism had a 38.4% lifetime rate of attempted suicide, whereas those without alcoholism had a 21.7% rate. Attempted suicide among subjects with bipolar disorder and alcoholism clustered in a subset of seven families. Families with alcoholic and suicidal probands had a 40.7% rate of attempted suicide in first-degree relatives with bipolar disorder, whereas other families had a 19.0% rate. CONCLUSIONS: Comorbid alcoholism was associated with a higher rate of attempted suicide among family members with bipolar disorder. Attempted suicide and alcoholism clustered in a subset of families. These relationships may have a genetic origin and may be mediated by intoxication, mixed states, and/or temperamental instability.


Assuntos
Alcoolismo/diagnóstico , Transtorno Bipolar/diagnóstico , Família , Tentativa de Suicídio/estatística & dados numéricos , Intoxicação Alcoólica/epidemiologia , Intoxicação Alcoólica/psicologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Comorbidade , Predisposição Genética para Doença , Humanos , Comportamento Impulsivo/epidemiologia , Comportamento Impulsivo/psicologia , Razão de Chances , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Fatores de Risco , Temperamento/classificação
16.
Mol Psychiatry ; 5(4): 439-42, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10889556

RESUMO

CTG18.1 is a highly polymorphic and unstable CTG repeat within an intron of the SEF2-1 gene. We tested the CTG18.1 repeat length in affective disorder, schizophrenia, and nonspecific ataxia; these diseases all have shown clinical evidence for anticipation. There was no difference in the allele frequencies comparing the controls and disease groups. The most common allele contains 11 CAGs (35%) followed by alleles with 14-17 CAGs (35%). There was no difference in the distribution of the alleles in the cases vs controls for ataxia (P = 0.11), affective disorders (P = 0.21), or schizophrenia (P = 0.26). The frequency of unstable CTG18.1 alleles was approximately 3% in a population of N. European descent and is not related to the phenotypes tested.


Assuntos
Ataxia/genética , Transtorno Bipolar/genética , Proteínas de Ligação a DNA , Desequilíbrio de Ligação , Esquizofrenia/genética , Transativadores/genética , Fatores de Transcrição , Repetições de Trinucleotídeos , Alelos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Humanos , Íntrons/genética , Masculino , Fatores de Transcrição TCF , Fator de Transcrição 4 , Proteína 2 Semelhante ao Fator 7 de Transcrição
17.
Am J Psychiatry ; 157(7): 1058-64, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10873911

RESUMO

OBJECTIVE: Point mutations in mitochondrial DNA (mtDNA) are one mechanism that could explain the apparent excess maternal transmission of bipolar affective disorder observed in some families. The authors sequenced the mtDNA from probands with bipolar disorder and tested nucleotide variants for association with the disorder. METHOD: The entire 16.5 kilobase mitochondrial genome was sequenced in nine unrelated probands selected from large pedigrees with exclusively maternal transmission of bipolar affective disorder. Compared to a reference sequence, variants were detected at 107 nucleotide positions. Fifteen variants of possible pathogenic significance were selected for further study. These variants were assayed in 93 unrelated probands with bipolar I, bipolar II, or schizoaffective-manic disorder and 63 comparison subjects, all of whom were classified into the major groups comprising the European mtDNA haplotype structure (haplogroups). RESULTS: The major European haplogroups were represented at the expected frequencies among both probands and comparison subjects. There was no significant difference between probands and comparison subjects in the frequency of any variant, although odds ratios >2 or <0.5 were observed for four variants. Frequencies of these four variants were similar in probands and haplogroup-matched comparison subjects. The results of all comparisons were essentially unchanged when probands from families with an apparently paternal transmission pattern were excluded. CONCLUSIONS: The results demonstrate that bipolar affective disorder occurs across all of the major European mtDNA haplogroups but do not reveal any point mutations that explain excess maternal transmission of the disorder.


Assuntos
Transtorno Bipolar/genética , DNA Mitocondrial/genética , Adolescente , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/epidemiologia , Estudos de Casos e Controles , Criança , Feminino , Ligação Genética/genética , Marcadores Genéticos , Variação Genética/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual/genética , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Cromossomo X/genética
18.
Am J Med Genet ; 96(1): 18-23, 2000 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-10686547

RESUMO

As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18-23, 2000


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 10 , Mapeamento Cromossômico , Feminino , Genótipo , Humanos , Escore Lod , Masculino , Linhagem
19.
Am J Hum Genet ; 66(1): 205-15, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10631152

RESUMO

A genome scan of approximately 12-cM initial resolution was done on 50 of a set of 51 carefully ascertained unilineal multiplex families segregating the bipolar affective disorder phenotype. In addition to standard multipoint linkage analysis methods, a simultaneous-search algorithm was applied in an attempt to surmount the problem of genetic heterogeneity. The results revealed no linkage across the genome. The results exclude monogenic models and make it unlikely that two genes account for the disease in this sample. These results support the conclusion that at least several hundred kindreds will be required in order to establish linkage of susceptibility loci to bipolar disorder in heterogeneous populations.


Assuntos
Transtorno Bipolar/genética , Genoma Humano , Humanos , Escore Lod , Modelos Genéticos , Linhagem , Fenótipo
20.
Bipolar Disord ; 2(1): 8-26, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11254025

RESUMO

OBJECTIVES: To review the methodologies and findings in the genetics of bipolar disorder (BPD), and to suggest future directions for research. METHODS: Reports of family, twin, adoption, linkage, association, cytogenetic, and animal model studies, and segregation analyses in English, were identified from multiple MEDLINE searches. Hand searches were carried out in bibliographies from review articles. RESULTS: Family, twin, and adoption studies have provided strong evidence for a genetic etiology in BPD. Early reports of linkage of BPD to DNA markers at several chromosomal sites have not proven robust, perhaps because of the complex nature of BPD inheritance. However, linkage findings in the 1990s, on chromosomes 18, 21q, 12q, and 4p, have provided leads that are being pursued through both genetic and physical mapping. No gene has yet been definitively implicated in BPD. CONCLUSIONS: Strategies for increasing the power to detect BPD genes include: (1) dividing the phenotype into genetically meaningful subtypes to decrease heterogeneity: and (2) ascertaining a very large family sample--a multicenter study now in progress will collect 700 bipolar I sibling pairs. BPD may result from several genes acting in concert so that new multilocus statistical methods could enhance the capacity to detect loci involved. Family-based association studies using a very large number of newly identified single nucleotide polymorphisms (SNPs) may allow for more efficient screening of the genome. As the Human Genome Project approaches its goal of isolating all genes by 2003, the data generated is likely to speed identification of candidate BPD genes.


Assuntos
Transtorno Bipolar/genética , Pesquisa/normas , Transtorno Bipolar/diagnóstico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 21/genética , Citogenética/métodos , Ligação Genética , Marcadores Genéticos/genética , Humanos , MEDLINE , Linhagem
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