RESUMEN
A genome-wide scan in 60 bipolar affective disorder (BPAD) affected sib-pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus-binding site for Six-family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine-mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family-based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 21/genética , Predisposición Genética a la Enfermedad/genética , Haplotipos/genética , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/genética , ADN/química , ADN/genética , Humanos , Desequilibrio de LigamientoRESUMEN
Bipolar disorder (BPD) is a complex genetic disorder with cycling symptoms of depression and mania. Despite the extreme complexity of this psychiatric disorder, attempts to localize genes which confer vulnerability to the disorder have had some success. Chromosomal regions including 4p16, 12q24, 18p11, 18q22, and 21q21 have been repeatedly linked to BPD in different populations. Here we present the results of a whole genome scan for linkage to BPD in an Irish population. Our most significant result was at 14q24 which yielded a non-parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P-value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22-24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE-Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders.
Asunto(s)
Trastorno Bipolar/genética , Ligamiento Genético , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 9/genética , Femenino , Predisposición Genética a la Enfermedad , Genómica , Humanos , Irlanda , Masculino , HermanosRESUMEN
Using a collection of Irish sib-pair nuclear families, we previously obtained modest evidence of linkage implicating 14q22-24 in bipolar disorder (BPD). To follow-up on this preliminary finding, an extended linkage analysis was performed which employed thirteen microsatellite markers, spanning a total distance of 85 cM on 14q. Effectively, P-values <0.05 were observed for a region extending over 41.88 cM, with the marker D14S281 displaying a peak multipoint non-parametric lod (NPL) score of 2.72 and an associated P-value of 0.003. Support for this finding was also obtained from flanking markers indicating excess allele sharing at 14q22-24 in Irish bipolar sib-pairs. A web-based candidate gene search of 14q22-24 resulted in the selection of GTP cyclohydrolase I (GCHI), located 200 kb 3' of D14S281, as the best plausible candidate gene for involvement in BPD. GCHI is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH(4)), a natural cofactor for tyrosine and tryptophan hydroxylases. These enzymes play an essential role in the biosynthesis of various hormones and neurotransmitters such as dopamine, noradrenaline, adrenaline, and serotonin. Numerous studies have also suggested that the clinical symptoms of depression might be related to a deficiency of BH(4). An association study between BPD and a novel single nucleotide polymorphism (SNP) in GCHI (G to A at position -959 bp, upstream of the ATG codon), is also presented here. This study revealed that the variant A allele is preferentially transmitted to BPI probands (chi(2) = 4.54, P = 0.033) suggesting that variants within GCHI may contribute to BPD in the Irish population.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 14/genética , GTP Ciclohidrolasa/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Alelos , Trastorno Bipolar/enzimología , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Genotipo , Humanos , Irlanda , Desequilibrio de Ligamiento , Repeticiones de Microsatélite , Mutación , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido SimpleRESUMEN
Recent evidence that 5HT-2A may be subjected to genomic imprinting prompted us to examine a collection of Irish family trios (an affected individual and both parents) for evidence of an association between 5HT-2A and bipolar disorder. Family trios offer an advantage over case control studies in regard to genomic imprinting since with family trios it is possible to trace the path of alleles from the parents to the offspring. Using haplotype-based haplotype relative risk (HHRR) and transmission/disequilibrium (TDT) analyses, no evidence was found for an association of 5HT-2A with bipolar affective disorder under the assumption of no imprinting and of imprinting.
Asunto(s)
Trastorno Bipolar/genética , Impresión Genómica , Receptores de Serotonina/genética , Alelos , ADN/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Masculino , Receptor de Serotonina 5-HT2ARESUMEN
Oestrogen, a sex steroid hormone, has long been hypothesized to be involved in alterations to pathways involved in neurotransmission, and therefore may be involved in neuropsychiatric conditions including bipolar disorder. Indeed, certain depressive disorders in women have been found to be associated with low levels of oestrogen and can be much improved by the administration of this hormone. As the effects of oestrogen are most probably mediated through the oestrogen receptors (ER alpha and ER beta), the genes encoding these receptors may be possible candidates for association studies with bipolar disorder and other neuropsychiatric disorders. A number of studies, including previous results from this group, have reported modest evidence of linkage between both bipolar disorder and schizophrenia and a region of chromosome 14 (q22-q24), where the ER beta gene has been localized. In the present study, a sample of 102 Irish parent-proband trios were genotyped for a single nucleotide polymorphism within the ER beta gene (3' untranslated region, A1730G). However, the transmission/disequilibrium test failed to reveal evidence of a distortion in allele transmission to bipolar I (BPI) probands.
Asunto(s)
Trastorno Bipolar/genética , Receptores de Estrógenos/genética , Distribución de Chi-Cuadrado , Cartilla de ADN , Trastorno Depresivo/genética , Receptor beta de Estrógeno , Femenino , Heterocigoto , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido SimpleRESUMEN
Conducting genome wide screens for evidence of genetic linkage has become a well-established method for identifying regions of the human genome harboring susceptibility loci for complex disorders. For bipolar disorder, a number of such studies have been performed, and several regions of the genome have potentially been implicated in the disorder. The classic design for a genome screen involves examining polymorphic genetic markers spaced at regular intervals throughout the genome, typically every 10 cM, for evidence of linkage. An alternative design, based on the observation that genes do not appear to be evenly distributed, was proposed, enabling the number of markers examined in a genome wide screen to be reduced. This article describes the application of such a modified screen to a collection of 48 Irish families with bipolar disorder, comprising a total of 82 affected sib-pairs. From the results obtained a number of regions are highlighted for further study. One of these regions (17q11.1-q12) coincides with the location of a candidate gene, the serotonin transporter, whereas others concur with the findings of published studies. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:728-732, 2000.
Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad/genética , Mapeo Cromosómico , ADN/genética , Salud de la Familia , Femenino , Genoma Humano , Humanos , Escala de Lod , Masculino , Repeticiones de MicrosatéliteRESUMEN
Previously we obtained modest linkage evidence implicating 17q11. 1-12 in bipolar disorder. A modified genome screen, based on gene-rich regions, on a collection of Irish sib-pair nuclear families revealed excess allele sharing at markers flanking the gene encoding the serotonin transporter (5-HTT; hSERT). Here we describe a study designed to combine the advantages of family-based association studies with the consideration of multiple polymorphic markers within a candidate gene. Ninety-two Irish families, with a total of 106 proband-parent trios, have been genotyped for 3 previously known polymorphisms within hSERT (5-HTTLPR, intron 2 VNTR, and 3' UTR G/T). Data from two and three polymorphic marker haplotypes revealed a number of marker combinations that showed evidence supportive of association; the most significant being for polymorphisms 5-HTTLPR and 3' UTR G/T (global chi(2), 12.91, df 3, P = 0.005). In addition, modest evidence of association also was observed for 5-HTTLPR alone. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:845-849, 2000.
Asunto(s)
Trastorno Bipolar/genética , Proteínas Portadoras/genética , Haplotipos , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Alelos , ADN/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Genotipo , Humanos , Masculino , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Catechol-O-methyltransferase (COMT) catalyses the methylation, and hence the inactivation, of catecholamines including the neurotransmitters dopamine and noradrenaline. There is evidence implicating COMT as a candidate gene for a number of neuropsychiatric conditions including bipolar disorder. A long recognized population variation in COMT activity exists and it has recently been established that variation in enzyme activity results from a polymorphic genetic variation within the COMT gene which can be readily assayed as a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP). A collection of 60 Irish bipolar I probands have been genotyped together with their parents. Tests comparing transmitted and non-transmitted alleles provide no evidence that the polymorphism contributes to a susceptibility to bipolar disorder within the sample as a whole. However, amongst female bipolar I probands (n = 30) there was a tendency for the low-activity allele of COMT to be preferentially transmitted. Furthermore, a re-examination of an Irish case-control sample resulted in a similar observation amongst female bipolar I sufferers and pooling the data sets strengthened the findings.
Asunto(s)
Trastorno Bipolar/genética , Catecol O-Metiltransferasa/genética , Cromosomas Humanos Par 22/genética , Alelos , Trastorno Bipolar/enzimología , Trastorno Bipolar/epidemiología , Estudios de Casos y Controles , Catecol O-Metiltransferasa/análisis , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos/genética , Humanos , Irlanda/epidemiología , Masculino , Padres , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , RiesgoRESUMEN
BACKGROUND: Disturbances in central nervous system Na+, K+ adenosine triphosphatase (ATPase) activity have previously been proposed as being involved in the pathophysiology of bipolar mood disorder. METHODS: We have examined one particular alpha subunit of this enzyme for allelic association in a sample of 85 Irish bipolar patients and 85 matched controls. RESULTS: There was evidence for an overall allelic association between the disease and a dinucleotide polymorphism within the ATP1A3 gene (p = .022). Subjects were then analyzed on the basis of a number of criteria, and the significance of the association increased when cases were divided based on the nature of the first episode. Patients who presented with a depressive episode first showed a significant association (p = .001) with this polymorphism. CONCLUSIONS: The results presented here provide preliminary evidence of an association between bipolar disorder and an alpha subunit of Na+, K+ ATPase, the expression of which predominates in the brain.
Asunto(s)
Trastorno Bipolar/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Adulto , Anciano , Alelos , Trastorno Bipolar/epidemiología , Trastorno Bipolar/fisiopatología , Encéfalo/metabolismo , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Repeticiones de Dinucleótido/genética , Femenino , Expresión Génica , Marcadores Genéticos , Humanos , Irlanda/epidemiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , ATPasa Intercambiadora de Sodio-Potasio/biosíntesis , ATPasa Intercambiadora de Sodio-Potasio/fisiologíaRESUMEN
The hypothesis that expanded trinucleotide repeats (TNRs) contribute to the pathogenesis of bipolar disorder has received strong support from recent studies showing that, on average, bipolar patients carry larger repeat sequences of the TNR motif CAG/CTG than do controls. It has been postulated that intergenerational expansion of a TNR may be responsible for the tendency for age of onset to become earlier in younger generations (anticipation) observed in some bipolar pedigrees, and that length polymorphism may account for variability in clinical phenotype. We have used the method of repeat expansion detection to examine these predictions in a sample of 133 Caucasian DSM-III-R bipolar I probands from the British Isles. We found no evidence to support the notion that CAG/CTG TNR genes are major determinants of phenotypic severity or age at onset in the population examined, and conclude that for most cases of bipolar disorder TNR genes may operate as susceptibility genes rather than as single genes of major effect.
Asunto(s)
Trastorno Bipolar/genética , Fenotipo , Repeticiones de Trinucleótidos/genética , Adulto , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: The purpose of this study was to identify the specific expanded CAG/CTG trinucleotide repeat associated with bipolar disorder. METHOD: The study employed an efficient multistage approach for using a genomic CAG/CTG screening set. RESULTS: The authors found no evidence of expanded repeats at 43 polymorphic autosomal loci and seven X chromosomal loci. Secondary screening was pursued at the only locus that contained a large allele (37 repeats) in the primary screening. No association was found between allele size and diagnostic status. CONCLUSIONS: It is highly unlikely that expansions in repeat size at any of the 50 candidate trinucleotide repeat loci examined are responsible for the association between expanded CAG/ CTG repeats and bipolar disorder. However, although the authors prioritized the repeats that were a priori most likely to be involved, the study does not reject the more general hypothesis that expanded CAG/CTG repeats are implicated in the pathogenesis of bipolar disorder.
Asunto(s)
Trastorno Bipolar/genética , Repeticiones de Trinucleótidos/genética , Alelos , Trastorno Bipolar/etiología , ADN/genética , Marcadores Genéticos , Genotipo , Humanos , Modelos Genéticos , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Cromosoma XRESUMEN
Recent studies have suggested that expanded CAG/CTG repeats contribute to the genetic aetiology of schizophrenia and bipolar disorder. However, the nature of this contribution is uncertain and difficult to predict from other known trinucleotide repeat diseases that display much simpler patterns of inheritance. We have sought to replicate and extend earlier findings using Repeat Expansion Detection in an enlarged sample of 152 patients with schizophrenia, 143 patients with bipolar disorder, and 160 controls. We have also examined DNA from the parents of 62 probands with schizophrenia or bipolar disorder. Our results confirm our earlier, preliminary findings of an association between expanded trinucleotide repeats and both schizophrenia and bipolar disorder. However, our data do not support the hypothesis that trinucleotide repeat expansion can alone explain the complex patterns of inheritance of the functional psychoses neither can this mechanism fully explain apparent anticipation.