RESUMO
AIMS: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample. METHODS: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models. RESULTS: There were no genes-environment associations. PRS-SZ was associated with positive dimensions (ß = 0.092, R2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension. CONCLUSIONS: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.
Assuntos
Transtornos Psicóticos , Esquizofrenia , Interação Gene-Ambiente , Humanos , Transtornos Psicóticos/genética , Transtornos Psicóticos/psicologia , Fatores de Risco , Esquizofrenia/genéticaRESUMO
Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Ritmo Circadiano/genética , Compostos de Lítio/uso terapêutico , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adulto , Transtorno Bipolar/metabolismo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Choque Térmico/genética , Humanos , Masculino , Pessoa de Meia-Idade , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. METHOD: A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken. RESULTS: The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. CONCLUSION: The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania.
Assuntos
Transtorno Bipolar/epidemiologia , Adulto , Idade de Início , Transtorno Bipolar/diagnóstico , Efeito de Coortes , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among 'SS' homozygotes (p = 0.002) but not among 'L' allele carriers. A history of at least one trauma decreased the AAO only in 'SS' homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and 'SS' genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and 'LS' genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype.
Assuntos
Idade de Início , Transtorno Bipolar/genética , Regiões Promotoras Genéticas , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/genética , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/patologia , Dopamina/metabolismo , Predisposição Genética para Doença/genética , Ácido Glutâmico/metabolismo , Núcleo Accumbens/metabolismo , Transdução de Sinais/fisiologia , Proteínas Vesiculares de Transporte de Glutamato/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Adulto , Animais , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/patologia , Autoadministração , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/genética , Proteínas Vesiculares de Transporte de Glutamato/deficiênciaRESUMO
The choice of an efficient psychotropic treatment for patients with schizophrenia is a key issue to improve prognosis and quality of life and to decrease the related burden and costs. As for other complex disorders, response to drugs in schizophrenia is highly heterogeneous and the underlying molecular mechanisms of this diversity are still poorly understood. In a carefully followed-up cohort of schizophrenic patients prospectively treated with risperidone or olanzapine, we used a specially designed single-nucleotide polymorphism (SNP) array to perform a large-scale genomic analysis and identify genetic variants associated with response to psychotropic drugs. We found significant associations between response to treatment defined by the reduction in psychotic symptomatology 42 days after the beginning of treatment and SNPs located in the chromosome 6, which houses the human leukocyte antigen (HLA). After imputation of the conventional HLA class I and class II alleles, as well as the amino-acid variants, we observed a striking association between a better response to treatment and a double amino-acid variant at positions 62 and 66 of the peptide-binding groove of the HLA-A molecule. These results support the current notion that schizophrenia may have immune-inflammatory underpinnings and may contribute to pave the way for personalized treatments in schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Antígenos HLA-A/genética , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Olanzapina , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Resultado do TratamentoRESUMO
Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR = 1.49 95%CI[1.18-1.88]; p = 0.0008) and rs782931 in RORA (OR = 1.31 95%CI[1.12-1.54]; p = 0.0006) and BD. Then we used a "reverse phenotyping approach" to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p = 0.04) and languid circadian type (p = 0.01), whereas rs782931 was associated with rigid circadian type (p = 0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.
Assuntos
Transtorno Bipolar/genética , Proteínas de Ciclo Celular/genética , Ritmo Circadiano/genética , Estudos de Associação Genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas CLOCK/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Humanos , MasculinoRESUMO
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).
Assuntos
Transtorno Bipolar/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 16/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Europa (Continente) , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Adulto JovemRESUMO
Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Hipocampo/patologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Biologia Computacional , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fenótipo , RNA Mensageiro/metabolismo , População Branca/genéticaRESUMO
Patients with bipolar disorder (BD) experience persistent circadian rhythm and sleep abnormalities during periods of remission, and biological studies have shown that these patients have abnormal melatonin secretion profiles or reactivity to light. We previously reported the association with BD of a common polymorphism (rs4446909) of the promoter of the acetylserotonin O-methyltransferase (ASMT) gene, encoding one of the two enzymes involved in melatonin biosynthesis. This variant was associated with weaker transcription and lower levels of ASMT activity in lymphoblastoid cell lines. Actigraphy, based on the use of a mobile portable device for the analysis of sleep/wake cycles in natural conditions, may be useful for studies of carriers of the at-risk allele. We studied the association between the ASMT rs4446909 variant and sleep/activity, as assessed with the Pittsburgh Sleep Quality Index (PSQI) and by actigraphy, in 53 subjects (25 patients with BD in remission and 28 healthy controls). The two groups were similar for age, sex ratio, current mood symptoms, body mass index and risk of sleep apnea syndrome. In the total sample, the GG at-risk genotype was associated with longer sleep duration (P = 0.03), greater activity in active periods of sleep (P = 0.015) and greater interday stability (P = 0.003). These associations remained significant when disease status was included in the model. Only the association with interday stability remained significant after correction for multiple testing. This pilot study thus shows that a BD-associated functional variant involved in the melatonin synthesis pathway influences sleep and circadian rhythms in bipolar patients in remission and controls.
Assuntos
Acetilserotonina O-Metiltransferasa/genética , Transtorno Bipolar/genética , Ritmo Circadiano , Polimorfismo de Nucleotídeo Único , Sono , Adulto , Transtorno Bipolar/diagnóstico , Estudos de Casos e Controles , Humanos , Projetos PilotoRESUMO
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of â¼750,000 high-quality genetic markers on a combined sample of â¼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of â¼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the â¼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Predisposição Genética para Doença , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Anquirinas/genética , Anquirinas/metabolismo , Antidepressivos/farmacologia , Povo Asiático/genética , Linhagem Celular Transformada , Citocinas/genética , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Lectinas/genética , Lectinas/metabolismo , Cloreto de Lítio/farmacologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , RNA Mensageiro/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Fatores de Tempo , Ácido Valproico/farmacologia , População Branca/genéticaRESUMO
Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.
Assuntos
Transtorno Bipolar/virologia , Variações do Número de Cópias de DNA/genética , Retrovirus Endógenos/genética , Genes env/genética , Esquizofrenia/virologia , Toxoplasmose/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Estudos de Casos e Controles , Retrovirus Endógenos/metabolismo , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esquizofrenia/sangue , Esquizofrenia/genéticaRESUMO
The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single- and multi-locus analyses. AKT1 and AKT2 protein levels were measured in post-mortem brain tissues from ante-mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five-SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 x 10(-4)) and bipolar disorder (P = 0.0041) and a four-SNP haplotype (TCGA) with the combined sample (1.73 x 10(-5)). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them.
Assuntos
Transtorno Bipolar/genética , Encéfalo/metabolismo , Haplótipos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Esquizofrenia/genética , Adulto , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-akt/metabolismo , Valores de Referência , Esquizofrenia/metabolismo , Estatísticas não ParamétricasRESUMO
Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Early-onset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.
Assuntos
Transtorno Bipolar/genética , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/metabolismo , Regiões Promotoras Genéticas/genética , Proteína 25 Associada a Sinaptossoma/genética , Adulto , Idade de Início , Transtorno Bipolar/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/biossíntese , Proteína 25 Associada a Sinaptossoma/biossínteseRESUMO
The identification of genetic factors underlying individual differences in antipsychotic drug response is of major interest. We investigated the involvement of two norepinephrine transporter gene polymorphisms in response to antipsychotics, comparing patients with strong and weak response to olanzapine and risperidone. We prospectively assessed short-term drug response in 75 Caucasian schizophrenic patients treated with these drugs, using the Positive and Negative Syndrome Scale. We then assessed the association between two SLC6A2 gene polymorphisms and drug response in this sample. No significant difference in genotype distribution was found between responders and non-responders, for the G1287A or T-182C polymorphism. The improvement in PANSS positive subscore was significantly greater in patients homozygous for the A1287 allele than in other patients, and significantly smaller in patients homozygous for the C-182 allele than in other patients. Our results suggest that these polymorphisms are specifically involved in the variation of positive symptoms in schizophrenic patients.
Assuntos
Antipsicóticos/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Esquizofrenia/tratamento farmacológico , Adulto , Benzodiazepinas , Feminino , Genótipo , Humanos , Masculino , Olanzapina , Farmacogenética , Polimorfismo Genético , Escalas de Graduação Psiquiátrica , RisperidonaRESUMO
Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.
Assuntos
Desequilíbrio de Ligação , Mães , Receptores de Ácido Caínico/genética , Esquizofrenia/genética , Alelos , Estudos de Casos e Controles , Cromossomos Humanos Par 6 , Suscetibilidade a Doenças , Feminino , Genômica , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Receptor de GluK2 CainatoRESUMO
A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.
Assuntos
Transtorno Autístico/genética , Cromossomos Humanos Par 6 , Ligação Genética , Receptores de Ácido Caínico/genética , Sequência de Aminoácidos , Encéfalo/fisiopatologia , Criança , Mapeamento Cromossômico , Éxons , Família , Feminino , Marcadores Genéticos , Genótipo , Ácido Glutâmico/fisiologia , Humanos , Masculino , Dados de Sequência Molecular , Fases de Leitura Aberta , Mapeamento por Restrição , Receptor de GluK2 CainatoRESUMO
The male to female ratio in autism is 4:1 in the global autistic population, but increases to 23:1 in autistic subjects without physical or brain abnormalities.(1) Despite this well-recognised gender difference, male predisposition to autistic disorder remains unexplained and the role of sex chromosomes is still debated. Numerical and structural abnormalities of the sex chromosomes are among the most frequently reported chromosomal disorders associated with autism. However, genome scans have failed to detect linkage on the X chromosome(2,3,4) and this approach cannot study the non-recombining region of the Y chromosome. In this study, we searched for a specific Y chromosome effect in autistic subjects. Using informative Y-polymorphic markers, the Y chromosome haplotypes of 111 autistic subjects from France, Sweden and Norway were defined and compared with relevant control populations. No significant difference in Y-haplotype distribution between the affected and control groups was observed. Although this study cannot exclude the presence of a Y susceptibility gene, our results are not suggestive of a Y chromosome effect in autism.
Assuntos
Transtorno Autístico/genética , Cromossomo Y , Criança , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Fatores SexuaisRESUMO
Capture of cellular mRNA by mobile elements has been an evolutionary catalyst for the spread of genes and a cause of cancer development. Here we present evidence that an orphan gene, FAM8A1 (family with sequence similarity 8), was captured by a retrovirus, followed by multiple retrotransposition events, during primate evolution between 45 and 58 million years ago. This represents the first record of cellular mRNA transduction in humans. The human gene is localized on chromosome 6p23 with five related pseudogenes (FAM8A2P-A6P), each inserted within a human endogenous retrovirus (HERV). Only the functional FAM8A1 gene is expressed and displays a ubiquitous mRNA and a testis-specific transcript present in the haploid phase of spermatogenesis. The structural features of the FAM8A1 pseudogenes include two short sequences of similarity between the FAM8A1 mRNA and the HERV sequences at both the 5' and 3' integration sites. These hallmarks suggest an alternative model to account for the capture of FAM8A1 cellular mRNA by HERV-K, involving illegitimate recombination events at the two sites of sequence similarity during reverse transcription. Unlike previous models, which assume at least one step of retroviral integration in the genome, our model is consistent with in vitro observations showing that multiple template switches occur among packaged viral transcripts. This leads to the speculation that, in some cases, cellular mRNAs may have been captured through similar processes involved in the retroviral life cycle.
Assuntos
Retrovirus Endógenos/genética , Evolução Molecular , Primatas/genética , Proteínas/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Bovinos , Galinhas , DNA/química , DNA/genética , DNA Complementar/química , DNA Complementar/genética , Feminino , Conversão Gênica , Expressão Gênica , Transferência Genética Horizontal , Humanos , Masculino , Proteínas de Membrana , Camundongos , Dados de Sequência Molecular , Mutação , Filogenia , Pseudogenes/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Distribuição Tecidual , Tartarugas , XenopusRESUMO
Several studies have reported significant linkage for schizophrenia on 6p23, with a maximum lod score between D6S274 and D6S285. In this paper, we present a new human kinesin gene localized in this 2-cM interval. This gene, termed KIF13A, belongs to the unc-104/KIF1A kinesin subfamily and represents the orthologue of Drosophila kinesin-73. Several alternative transcripts are differentially expressed in human tissues, probably reflecting differences in cargo binding and transport of corresponding proteins. During early mouse development, its homologue (Kif13A) is expressed essentially in the central nervous system. In Caenorhabditis elegans, the unc-104 gene is involved in axonal anterograde transport, and null mutants present several behavioral defects. The putative function and genomic localization of KIF13A make this gene an interesting candidate for genetic predisposition to schizophrenia. We provide sequences of 20 single-nucleotide polymorphisms localized within KIF13A to test for association studies between this gene and schizophrenia.