RESUMEN
Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function.
Asunto(s)
Trastornos Mentales/genética , Trastornos Mentales/patología , MicroARNs/genética , Repeticiones de Minisatélite/genética , Neurogénesis/genética , Transmisión Sináptica/genética , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Masculino , MicroARNs/metabolismo , Análisis por Micromatrices , Modelos Moleculares , Neuroblastoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Suecia , TransfecciónRESUMEN
We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia.
Asunto(s)
Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Esquizofrenia/genética , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 10 , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Adulto JovenRESUMEN
Regions that show task-induced deactivations may be part of a default-mode network related to processes that are more engaged during passive than active task conditions. Alteration of task-induced deactivations with age and dementia is indicated by atypical engagement of default-mode network regions. Genetic studies show a relation between the apolipoprotein E4 (APOE4) allele and the common form of Alzheimer's disease (AD), and altered functional brain activation has been observed in non-demented APOE4 carriers compared to non-carriers. Here we investigate the hypothesis of altered default-mode network brain responses in individuals with genetic risk for AD. Functional MRI was used to assess task-induced deactivation in 60 subjects of which 30 carried at least one copy of the APOE4 allele, and 30 non-carriers. Subjects were scanned while performing a semantic categorization task shown to promote episodic memory encoding. The results show patterns of deactivation consistent with the default-mode network. We also found reduced deactivation in non-demented APOE4 carriers compared to non-carriers, suggesting alterations in the default-mode network in the absence of dementia. These results implicate possibilities for investigating altered properties of task-induced deactivations in individuals with genetic risk for AD, and may prove useful for pre-clinical identification of individuals susceptible to memory problems and AD.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Apolipoproteína E4 , Mapeo Encefálico , Encéfalo/patología , Anciano , Enfermedad de Alzheimer/patología , Encéfalo/irrigación sanguínea , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Memoria/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Oxígeno/sangre , SemánticaAsunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de la Mielina/genética , Mutación Puntual , Polimorfismo Genético , Células 3T3 , Animales , Femenino , Humanos , Masculino , Metionina , Ratones , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Suecia , TreoninaRESUMEN
There is bidirectional comorbidity between anxiety/depression and irritable bowel syndrome (IBS). To investigate the prevalence of IBS symptoms, and factors associated with gastrointestinal symptoms in patients with recurrent depressive disorder. Patients (n = 95) with recurrent type of major depression according to DSM-IV criteria and sex- and age-matched controls (n = 190) were sent questionnaires investigating symptoms of IBS [Gastrointestinal Symptom Rating Scale (GSRS)-IBS] and symptoms of anxiety and depression [Hospital Anxiety and Depression Scale (HADS)]. Medical records were checked over a 10-year period for chronic somatic symptoms or diseases. Seventy-three patients with unipolar disorder (mean age 63.6 years SD 13.8; range 23-86 years) and 156 controls (mean age 59.2 years SD 11.6, range 21-85 years) responded. Patients with recurrent depression had higher GSRS-IBS scores and showed a strong correlation between symptoms of IBS and anxiety-depression (r(s) = 0.54; P < 0.001). IBS symptoms were also associated with multiple pain symptoms, higher health-seeking behaviour and selective-serotonin-reuptake inhibitor intake. However, patients with recurrent depression (n = 46) in remission (HADS-Depression score <8) did not have more symptoms of IBS than controls (GSRS-IBS median score 6.0 vs 6.5; P = 0.46). There is a strong association between symptoms of IBS and symptoms of anxiety and depression, whereas depressive patients in remission do not have more IBS symptoms than controls.
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Depresión/complicaciones , Depresión/fisiopatología , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/complicaciones , Ansiedad/fisiopatología , Estudios de Casos y Controles , Depresión/psicología , Femenino , Encuestas Epidemiológicas , Humanos , Síndrome del Colon Irritable/psicología , Masculino , Persona de Mediana Edad , Prevalencia , Recurrencia , Remisión Espontánea , Índice de Severidad de la EnfermedadRESUMEN
Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
Asunto(s)
Trastorno Bipolar/genética , Trastorno de Personalidad Limítrofe/genética , Trastorno Depresivo Mayor/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Adulto JovenRESUMEN
The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (ß=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (ß=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (ß=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE É4 non-carriers (ß=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (ß=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (ß=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in É4-carriers (ß=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE É4-carriers might be at differential risk.
Asunto(s)
Disfunción Cognitiva/genética , Análisis de la Aleatorización Mendeliana , Telómero/genética , Población Blanca/genética , Adulto , Anciano , Apolipoproteína E4/genética , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Femenino , Tamización de Portadores Genéticos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Psicometría , Estadística como AsuntoRESUMEN
Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Quinasas Ciclina-Dependientes/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Anciano , Quinasa 5 Dependiente de la Ciclina , Análisis Mutacional de ADN , Exones/genética , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas , Variación Genética/genética , Genotipo , Haplotipos , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Países Bajos , SueciaRESUMEN
BACKGROUND: Seasonal affective disorder (SAD) has been regarded as a melatonin disorder, but the pathophysiological mechanisms of SAD are to a large extent unclarified. Serotonergic mechanisms have also been studied, but they have shown inconsistent results. METHODS: We have compared [3H]paroxetine and [3H]lysergic acid diethylamide (LSD) binding in platelets from 23 SAD patients and 23 controls. Then SAD patients had 4 weeks of light therapy. On the last treatment day new blood samples were drawn. Symptoms before and after light treatment were measured by SIGH-SAD. RESULTS: Bmax for paroxetine binding before light treatment was higher in SAD patients compared to controls and also higher in responders than in nonresponders. Bmax decreased significantly during light treatment. We also found a negative correlation between the two Bmax values before but not after light treatment. There was a negative correlation between Bmax for paroxetine binding before treatment and clinical status after treatment. Patients with reduced Bmax for LSD binding after treatment had a better clinical treatment response. CONCLUSIONS: The present study indicates that serotonin receptor parameters might be suitable in the prediction of clinical response to light treatment.
Asunto(s)
Plaquetas/metabolismo , Dietilamida del Ácido Lisérgico/metabolismo , Paroxetina/metabolismo , Fototerapia , Trastorno Afectivo Estacional/sangre , Trastorno Afectivo Estacional/terapia , Serotoninérgicos/metabolismo , Serotonina/fisiología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis de Regresión , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismoRESUMEN
Lithium therapy response and age of onset (AOO) were studied in 98 patients with bipolar affective disorder (BPAD) who were divided into subgroups depending on type of family history of affective disorders. The highest (33.0 years) and lowest (25.5 years) age of onset were found in nonfamilial patients and in familial patients with a first-degree relative of BPAD, respectively. Nonfamilial patients showed the best response to lithium. There were 0.9 episodes/year off lithium compared to 0.3 episodes/year on lithium (an 88% decrease). A poorer response (a 71% decrease; a reduction from 1.39 episodes per year off lithium to 0.65 on lithium) was found in familial patients with a first-degree relative of BPAD. Differences in serum lithium values between the groups could not explain the observed differences. Thus, familial patients showed a more severe manifestation of the disease with an earlier AOO and a lower prophylactic effect of lithium.
Asunto(s)
Antimaníacos/uso terapéutico , Litio/uso terapéutico , Trastornos del Humor/genética , Trastornos del Humor/prevención & control , Edad de Inicio , Antimaníacos/sangre , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/psicología , Femenino , Humanos , Litio/sangre , Masculino , Persona de Mediana Edad , Escalas de Valoración PsiquiátricaRESUMEN
Clinical anticipation has been reported in bipolar affective disorder (BPAD). The hypothesis that expanded trinucleotide repeats are related to anticipation and transmission pattern in families with bipolar affective disorder is tested in this study. Eighty-seven two-generation pairs of patients recruited from 29 bipolar families were analyzed. The repeat expansion detection method was used to detect CAG repeat expansions between successive generations. Significant changes in age at onset and episode frequency in successive generations were observed. Mean trinucleotide CAG repeat length between parental and offspring generation significantly increased when the phenotype increased in severity, i.e., changed from major depression, single episode or unipolar recurrent depression to BPAD. A parent-of-origin effect was also observed with a significant increase in median length CAG between G1 and G2 with maternal inheritance. This increase was observed notably in female offspring. Our findings indicate for the first time that expansion of CAG repeat length could explain the clinical observation of anticipation in families with BPAD. These results provide further support for expanded trinucleotide repeat sequences as risk factors in major affective disorders.
Asunto(s)
Trastorno Bipolar/genética , Repeticiones de Trinucleótidos/genética , Adulto , Edad de Inicio , Trastorno Bipolar/epidemiología , Trastorno Bipolar/psicología , ADN/análisis , ADN/genética , Femenino , Humanos , Masculino , FenotipoRESUMEN
BACKGROUND: Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS: No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.
Asunto(s)
Trastorno Bipolar , Trastorno Depresivo , Polimorfismo Genético/genética , Intento de Suicidio/psicología , Intento de Suicidio/estadística & datos numéricos , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismo , Alelos , Trastorno Bipolar/enzimología , Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Análisis Mutacional de ADN , Cartilla de ADN/genética , Trastorno Depresivo/enzimología , Trastorno Depresivo/genética , Trastorno Depresivo/psicología , Europa (Continente)/epidemiología , Expresión Génica , Genotipo , Humanos , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
To investigate whether mitochondrial mutations underly susceptibility to schizophrenia, we sequenced the mtDNAs of two unrelated Swedish patients with schizophrenia and low cytochrome oxidase activity and two maternally related Scottish patients from a family with suspected maternal inheritance of the disease. We found five substitutions in coding regions that have not previously been described as polymorphisms. These new substitutions were studied in 81 schizophrenic patients and five control groups from Sweden and Scotland and found to differ in frequency between populations, emphasizing the importance of using large and well-defined control materials for evaluating the association of mtDNA mutations with disease. The results do not lend strong support to the association of a particular mtDNA substitution with increased risk for schizophrenia. However, the trend towards a higher frequency of substitutions in the patients deserves further attention.
Asunto(s)
ADN Mitocondrial/genética , Esquizofrenia/genética , Secuencia Conservada/genética , Deficiencia de Citocromo-c Oxidasa , Análisis Mutacional de ADN , Cartilla de ADN/genética , Humanos , Mutación/genética , Linaje , Polimorfismo Genético/genética , Factores de Riesgo , Escocia , Análisis de Secuencia de ADN , SueciaRESUMEN
Platelet serotonin (5-hydroxytryptamine, 5-HT) uptake sites were studied in a control group (n = 30) and an Alzheimer group (n = 40) using [3H]paroxetine as radioligand. The maximum number of binding sites (Bmax) for control (1250 +/- 60 fmol/mg protein) was not different from the Alzheimer group (1280 +/- 40 fmol/mg protein). There were no differences in apparent binding affinity (Kd): 0.046 (0.024-0.062) nM for control and 0.040 (0.027-0.061) nM for Alzheimer. Thus even though several previous studies have demonstrated marked atrophy of 5-HT containing neurites and 5-HT uptake sites in Alzheimer's disease, these findings are not found in the periphery on platelets. The platelet 5-HT uptake site cannot be used as a peripheral marker of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/sangre , Plaquetas/metabolismo , Piperidinas/metabolismo , Receptores de Serotonina/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Imipramina/metabolismo , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Paroxetina , Piperidinas/farmacocinética , Ensayo de Unión Radioligante , Caracteres SexualesRESUMEN
In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Gangliósidos/metabolismo , Neurotransmisores/metabolismo , Receptores Muscarínicos/metabolismo , Anciano , Enfermedad de Alzheimer/patología , Encéfalo/enzimología , Encéfalo/patología , Colina O-Acetiltransferasa/metabolismo , Femenino , Ácido Homovanílico/metabolismo , Humanos , Ácido Hidroxiindolacético/metabolismo , Isoenzimas/metabolismo , Masculino , Metoxihidroxifenilglicol/metabolismo , Monoaminooxidasa/metabolismo , Neurofibrillas/ultraestructura , Serotonina/metabolismoRESUMEN
Several reports have indicated genetic linkage between markers on the short arm of chromosome 6 and schizophrenia. However, significant threshold levels were not always achieved, and the chromosomal regions identified are large and different in different families. One way to decrease the problem of heterogeneity is to study a single extended pedigree. Here we report the analysis of a very large, previously undescribed pedigree from northern Sweden that includes 31 affected individuals. We typed 16 markers spanning 40 cM on the short arm of chromosome 6. Linkage analysis was performed only with the affected individuals. Suggestive lod scores (maximum 2.6) were obtained with markers on chromosome 6p23 in a single branch of the large pedigree indicating possible heterogeneity inside the family. A haplotype comprising markers from D6S309 to D6S1578 was found to segregate with the disease. This chromosomal region is included within a segment proposed to contain a susceptibility gene for schizophrenia by many other investigators. Our results thus give further support for a possible localization of a susceptibility locus for schizophrenia in 6p23 and help to narrow the candidate chromosomal region to the segment included between markers D6S309 and D6S1578.
Asunto(s)
Cromosomas Humanos Par 6 , Ligamiento Genético , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Alelos , Femenino , Marcadores Genéticos , Genotipo , Humanos , Escala de Lod , Masculino , Modelos Estadísticos , Linaje , SueciaRESUMEN
Expansion at a recently identified unstable trinucleotide repeat on chromosome 13q21 has been reported as the molecular cause for spinocerebellar ataxia type 8 (SCA8). The trinucleotide repeat, which consists of a [CTA]n repeat and adjacent [CTG]n repeat, was reported to have a pathogenic range of 107-127 CTG repeats (or 110-130 combined CTA and CTG repeats) in a large ataxia kindred. This repeat region was also cloned by our group from a bipolar affective disorder (BPAD) patient, who has approximately 600 combined repeats, and large alleles (>100 repeats) were reported to be present in 0.7% of controls and 1.5% of major psychosis patients (n = 710 and n = 1,120, respectively). We have followed up these findings by screening three new samples of BPAD and schizophrenia (SCZ) patients and controls, including 272 individuals from 14 BPAD families from Sweden, 130 individuals from 32 SCZ and BPAD families/trios from the Azores Islands, and 206 SCZ individuals from the United Kingdom and Ireland, and 219 matched controls. We found large repeat alleles above the SCA8 pathogenic range in individuals from 3 of 32 Azorean pedigrees and in 1 of 206 SCZ individuals from the United Kingdom, and repeat alleles within the SCA8 pathogenic range in 1 of 14 Swedish families. Although the rarity of major psychosis patients carrying the SCA8 expansion mutation would require a much larger sample size to reach statistical significance, these results support the previously reported observation of increased occurrence of large repeats at SCA8 in major psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:873-876, 2000.
Asunto(s)
Proteínas del Tejido Nervioso/genética , Trastornos Psicóticos/genética , Repeticiones de Trinucleótidos/genética , Alelos , ADN/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , ARN Largo no Codificante , ARN no TraducidoRESUMEN
Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.
Asunto(s)
Trastorno Bipolar/genética , Fenotipo , Polimorfismo Genético , Tirosina 3-Monooxigenasa/genética , Adulto , Edad de Inicio , Alelos , Estudios de Casos y Controles , Europa (Continente) , Europa Oriental , Femenino , Variación Genética , Heterocigoto , Homocigoto , Humanos , Israel , Masculino , Persona de Mediana EdadRESUMEN
As part of the European Multicentre Association Study of Schizophrenia (EMASS), we studied polymorphisms in the dopamine DRD2 and DRD3 receptor genes. The EMASS collaboration was established to create a large, statistically powerful sample of schizophrenic patients and controls from different European centres. Previous studies have suggested associations between schizophrenia and the Ser311Cys polymorphism in exon 7 of the dopamine DRD2 receptor gene [Arinami et al., (1994): Lancet 343:703-704] and a polymorphism Ser9gly in exon 1 of the dopamine DRD3 receptor gene [Crocq et al. (1992): J Med Genet 29:858-860]. We tested for these associations in samples of 373 and 413, and 311 and 306 patients and controls, respectively. We found no evidence for allelic association between schizophrenia and the Cys311 variant of the DRD2 receptor gene and no homozygotes for this variant were observed by any group. However, an excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi2 = 8.54, P = 0.003, odds ratio = 1.64, 95% CI = 1.18-2.29). We also observed a significant excess of the 1-1 (Ser9Ser) genotype (chi2 = 8.13, P = 0.004, odds ratio = 1.7, 95% CI = 1.18-2.4). No evidence of heterogeneity between samples was detected and there was no evidence of an allelic association. These findings suggest that the rare Cys311 variant in exon 7 of the DRD2 receptor gene does not play a role in the pathogenesis of schizophrenia in European populations. Currently, our results do support the previous findings of an association between increased homozygosity of the Ser/Gly variant of the Dopamine D3 receptor gene and schizophrenia.