RESUMEN

Background: Recent advances in resting-state fMRI allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. However, most dynamic studies still use subject-specific, spatially-static nodes. As recent studies have demonstrated, incorporating time-resolved spatial properties is crucial for precise functional connectivity estimation and gaining unique insights into brain function. Nevertheless, estimating time-resolved networks poses challenges due to the low signal-to-noise ratio, limited information in short time segments, and uncertain identification of corresponding networks within and between subjects. Methods: We adapt a reference-informed network estimation technique to capture time-resolved spatial networks and their dynamic spatial integration and segregation. We focus on time-resolved spatial functional network connectivity (spFNC), an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to multi-factorial genomic data. Results: Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and align with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spFNC exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and correlates with genetic risk for schizophrenia. This dysfunction is also reflected in high-dimensional (voxel-level) space in regions with weak functional connectivity to corresponding networks. Conclusions: Our method can effectively capture spatially dynamic networks, detect nuanced SZ effects, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the potential of dynamic spatial dependence and weak connectivity in the clinical landscape.

RESUMEN

Transposable elements (TEs) are low-complexity elements (e.g., LINEs, SINEs, SVAs, and HERVs) that make up to two-thirds of the human genome. There is mounting evidence that TEs play an essential role in molecular functions that influence genomic plasticity and gene expression regulation. With the advent of next-generation sequencing approaches, our understanding of the relationship between TEs and psychiatric disorders will greatly improve. In this chapter, the Authors comprehensively summarize the state-of the-art of TE research in animal models and humans supporting a framework in which TEs play a functional role in mechanisms affecting a variety of behaviors, including neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Finally, the Authors discuss recent therapeutic applications raised from the increasing experimental evidence on TE functional mechanisms.

Asunto(s)

Elementos Transponibles de ADN , Genómica , Animales , Regulación de la Expresión Génica , Genoma Humano , Humanos

RESUMEN

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Asunto(s)

Encéfalo/patología , Esquizofrenia/patología , Adulto , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Estudios de Casos y Controles , Femenino , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Estudios Prospectivos , Esquizofrenia/genética

RESUMEN

Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.

Asunto(s)

Enfermedad de Huntington/líquido cefalorraquídeo , Enfermedad de Huntington/genética , Mutación , Proteínas del Tejido Nervioso/genética , Péptidos/líquido cefalorraquídeo , Agregación Patológica de Proteínas/líquido cefalorraquídeo , Animales , Células Cultivadas , Femenino , Humanos , Proteína Huntingtina , Masculino , Microscopía Electrónica , Agregación Patológica de Proteínas/patología , Ratas , Ratas Transgénicas , Transfección

Asunto(s)

Autorreceptores/metabolismo , Neuronas Dopaminérgicas/fisiología , Corteza Prefrontal/fisiopatología , Receptores de Dopamina D2/metabolismo , Animales , Autorreceptores/genética , Conducta Animal/fisiología , Cromatina/metabolismo , Proteínas de Unión al ADN , Epigénesis Genética , Expresión Génica , Histonas/metabolismo , Metilación , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Dopamina D2/genética

RESUMEN

Alterations of the dopaminergic system are associated with the cognitive and functional dysfunctions that characterize complex neuropsychiatric disorders. We modeled a dysfunctional dopaminergic system using mice with targeted ablation of dopamine (DA) D2 autoreceptors in mesencephalic dopaminergic neurons. Loss of D2 autoreceptors abolishes D2-mediated control of DA synthesis and release. Here, we show that this mutation leads to a profound alteration of the genomic landscape of neurons receiving dopaminergic afferents at distal sites, specifically in the prefrontal cortex. Indeed, we observed a remarkable downregulation of gene expression in this area of ~2000 genes, which involves a widespread increase in the histone repressive mark H3K9me2/3. This reprogramming process is coupled to psychotic-like behaviors in the mutant mice. Importantly, chronic treatment with a DA agonist can revert the genomic phenotype. Thus, cortical neurons undergo a profound epigenetic reprogramming in response to dysfunctional D2 autoreceptor signaling leading to altered DA levels, a process that may underlie a number of neuropsychiatric disorders.

Asunto(s)

Autorreceptores/metabolismo , Cuerpo Estriado/fisiopatología , Neuronas Dopaminérgicas/fisiología , Epigénesis Genética , Corteza Prefrontal/fisiopatología , Receptores de Dopamina D2/metabolismo , Animales , Autorreceptores/genética , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Regulación hacia Abajo , Expresión Génica , Histonas/metabolismo , Ratones Transgénicos , Corteza Prefrontal/efectos de los fármacos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/fisiopatología , Quinpirol/farmacología , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/genética

RESUMEN

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.

Asunto(s)

Progresión de la Enfermedad , Genes MHC Clase I/genética , Infecciones por VIH/genética , VIH-1 , Polimorfismo de Nucleótido Simple , Proteínas de Unión al ADN/genética , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Complejo Mayor de Histocompatibilidad/genética , ARN Largo no Codificante , ARN no Traducido , Factores de Tiempo , Factores de Transcripción/genética

RESUMEN

Complement receptor 1 (CR1) levels have been associated with malarial susceptibility and/or severity of the disease in different population groups, and CR1 is a receptor for Plasmodium falciparum. In this study, multiple CR1 single-nucleotide polymorphisms (SNPs) showed strong evidence of population differentiation between Sardinian and other European ethnic groups. Cross population algorithms comparing haplotype structure and differences in haplotype and allele frequency distribution provided additional support for natural selection of CR1 in Sardinia. The predominant Sardinian CR1 haplotype included SNPs that are associated with decreased CR1 levels in Europeans and other population groups. Previous studies have shown that the SNPs within the dominant Sardinian haplotype have a significantly higher frequency in a malaria endemic compared with non-endemic regions in India. Together with the historical evidence of the prevalence of malaria in Sardinia, these data support the role of malaria leading to positive selection of this CR1 haplotype in Sardinia.

Asunto(s)

Haplotipos , Malaria Falciparum/genética , Receptores de Complemento 3b/genética , Selección Genética , Algoritmos , Predisposición Genética a la Enfermedad , Humanos , Italia , Malaria Falciparum/epidemiología , Modelos Estadísticos , Plasmodium falciparum/inmunología , Polimorfismo de Nucleótido Simple , Receptores de Complemento 3b/inmunología , Población Blanca/genética

RESUMEN

We have discovered two genes, RSRC1 and ARHGAP18, associated with schizophrenia and in an independent study provided additional support for this association. We have both discovered and verified the association of two genes, RSRC1 and ARHGAP18, with schizophrenia. We combined a genome-wide screening strategy with neuroimaging measures as the quantitative phenotype and identified the single nucleotide polymorphisms (SNPs) related to these genes as consistently associated with the phenotypic variation. To control for the risk of false positives, the empirical P-value for association significance was calculated using permutation testing. The quantitative phenotype was Blood-Oxygen-Level Dependent (BOLD) Contrast activation in the left dorsal lateral prefrontal cortex measured during a working memory task. The differential distribution of SNPs associated with these two genes in cases and controls was then corroborated in a larger, independent sample of patients with schizophrenia (n=82) and healthy controls (n=91), thus suggesting a putative etiological function for both genes in schizophrenia. Up until now these genes have not been linked to any neuropsychiatric illness, although both genes have a function in prenatal brain development. We introduce the use of functional magnetic resonance imaging activation as a quantitative phenotype in conjunction with genome-wide association as a gene discovery tool.

Asunto(s)

Proteínas Activadoras de GTPasa/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/irrigación sanguínea , Esquizofrenia/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Esquizofrenia/patología , Adulto Joven

RESUMEN

To clarify the role of gene polymorphisms on the effect of losartan and losartan plus hydrochlorothiazide on blood pressure (primary end point) and on cardiac, vascular and metabolic phenotypes (secondary end point) after 4, 8, 12, 16 and 48 weeks treatment, an Italian collaborative study - The Study of the Pharmacogenomics in Italian hypertensive patients treated with the Angiotensin receptor blocker losartan (SOPHIA) - on never-treated essential hypertensives (n = 800) was planned. After an 8 week run-in, losartan 50 mg once daily will be given and doubled to 100 mg at week +4 if blood pressure is more than 140/90 mmHg. Hydroclorothiazide 25 mg once daily at week +8 and amlodipine 5 mg at week +16 will be added if blood pressure is more than 140/90 mmHg. Cardiac mass (echocardiography), carotid intima-media thickness, 24 h ambulatory blood pressure, homeostatic model assessment (HOMA) index, microalbuminuria, plasma renin activity and aldosterone, endogenous lithium clearance, brain natriuretic peptide and losartan metabolites will be evaluated. Genes of the renin-angiotensin-aldosterone system, salt sensitivity, the beta-adrenergic system and losartan metabolism will be studied (Illumina custom arrays). A whole-genome scan will also be performed in half of the study cohort (1M array, Illumina 500 GX beadstation).

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II , Ensayos Clínicos como Asunto/métodos , Hipertensión , Losartán , Farmacogenética/métodos , Proyectos de Investigación , Adolescente , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Ensayos Clínicos como Asunto/normas , Determinación de Punto Final , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/farmacocinética , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Losartán/efectos adversos , Losartán/farmacocinética , Losartán/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Farmacogenética/normas , Polimorfismo Genético

RESUMEN

Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bgamma-regulatory subunit of the protein phosphatase 2A (PP2A-Bgamma). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bgamma subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K+ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bgamma subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3beta) is considered as an interesting target of lithium, the classical drug used in BD. GSK3beta phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li+.

Asunto(s)

Trastorno Bipolar/genética , Trastorno Bipolar/metabolismo , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ2/metabolismo , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas Fosfatasas/metabolismo , Tálamo/metabolismo , Animales , Antimaníacos/farmacología , Argentina , Células COS , Estudios de Casos y Controles , Chlorocebus aethiops , Inhibidores Enzimáticos/farmacología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Haplotipos , Humanos , Desequilibrio de Ligamiento , Cloruro de Litio/farmacología , Potenciales de la Membrana , Oportunidad Relativa , Fosforilación , Polimorfismo de Nucleótido Simple , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Fosfatasa 2 , Medición de Riesgo , Factores de Riesgo , Tálamo/efectos de los fármacos , Transfección , Reino Unido

Asunto(s)

Proteínas de Ciclo Celular/genética , Cromosomas Humanos Par 6/genética , Predisposición Genética a la Enfermedad , Proteínas Nucleares/genética , Esquizofrenia/genética , Genotipo , Humanos , Escala de Lod , Linaje , Polimorfismo de Nucleótido Simple/genética , Receptores Acoplados a Proteínas G

RESUMEN

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.

Asunto(s)

Arildialquilfosfatasa/genética , Trastorno Autístico/enzimología , Trastorno Autístico/genética , Arildialquilfosfatasa/metabolismo , Trastorno Autístico/etiología , Secuencia de Bases , Estudios de Casos y Controles , Niño , ADN/genética , Análisis Mutacional de ADN , Ambiente , Femenino , Variación Genética , Humanos , Insecticidas/metabolismo , Italia , Desequilibrio de Ligamiento , Masculino , Modelos Biológicos , Organofosfatos/metabolismo , Péptidos/orina , Polimorfismo de Nucleótido Simple , Proteína Reelina , Serotonina/sangre , Estados Unidos

RESUMEN

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.

Asunto(s)

Cromosomas Humanos Par 15/genética , Dislexia/genética , Predisposición Genética a la Enfermedad/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Niño , Mapeo Cromosómico , Proteínas del Citoesqueleto , Ligamiento Genético , Marcadores Genéticos , Genotipo , Humanos , Fenotipo , Lectura , Hermanos , Conducta Verbal/fisiología

RESUMEN

SUMMARY: PedSplit facilitates pedigree management for gene-gene interaction and sex specific tests for increased homogeneity within subgroups. PedSplit also provides a simple approach for calculating haplotype relative risk and generating internal 'controls'. AVAILABILITY: Executables, C++ source code and documentation for PedSplit can be downloaded from http://www.pharmacogenetics.ca in the links and software section.

Asunto(s)

Mapeo Cromosómico/métodos , Análisis Mutacional de ADN/métodos , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Linaje , Medición de Riesgo/métodos , Programas Informáticos , Algoritmos , Frecuencia de los Genes/genética , Variación Genética/genética , Haplotipos/genética , Internet , Desequilibrio de Ligamiento/genética , Factores de Riesgo , Factores Sexuales

RESUMEN

The aim of the present study was to investigate impairment in social adjustment and self-esteem of bipolar patients (n=144) in remission for at least 3 months. Patients were recruited among four different centres: Sofia, Athens, Jerusalem and Milan, and were individually matched to control subjects in relation to sex, age and geographical origin. Subjects completed the Rosenberg self-esteem scale (SES) and the self-report version of the social adjustment scale (SAS). Bipolar patients reported to experience more difficulties in social adjustment than controls, specifically for leisure and work activities. Further, our results show that bipolar patients have significantly lower self-esteem compared to controls, even after remission.

Asunto(s)

Trastorno Bipolar/psicología , Autoimagen , Ajuste Social , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Schizophrenia is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide significance. We systematically recruited Arab Israeli families multiply affected with schizophrenia from the catchment area of a Regional Mental Health Center. Clinical diagnoses were established by semistructured interviews and all other available sources of information under narrow, core and broad categories. Using 350 microsatellite markers, spaced at an average of 10.3 cM, we performed an autosomal scan in 155 subjects from 21 families. Linkage analysis employed affects only, multipoint, nonparametric (model-free) and also parametric (dominant and recessive) approaches. We detected significant evidence for a schizophrenia susceptibility gene at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) under the broad diagnostic category and a parametric LOD score of 3.33 (dominant model). Under the core diagnostic category the NPL was 4.29 (P=0.00001) and the LOD score 4.16 (dominant model). We also detected suggestive evidence for linkage at chromosome 10q24 under the broad diagnostic category (NPL 3.24, P=0.0008; heterogeneity LOD score, dominant model 2.65, alpha=0.82). Additionally, NPL scores >2.0 were observed at chromosome 2q37, 4p15-16, 7p22, 9q21-22 and 14q11.1-11.2. The linkage we detected at chromosome 6q23 fulfills the criteria for genome-wide significance and is located approximately midway between loci suggested by a previous significant report at chromosome 6q25 and findings located more centromerically at 6q21-22.

Asunto(s)

Árabes/genética , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 6 , Escala de Lod , Esquizofrenia/genética , Salud de la Familia , Predisposición Genética a la Enfermedad , Genoma Humano , Genotipo , Humanos , Israel

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo/genética , Desequilibrio de Ligamiento , Esquizofrenia/genética , Humanos

RESUMEN

Although the genetic contribution to schizophrenia is substantial, positive findings in whole-genome linkage scans have not been consistently replicated. We analyzed gene expression in various rat conditions to identify novel candidate genes for schizophrenia. Suppression subtraction hybridization (SSH), with polyA mRNA from temporal and frontal cortex of rats, was used to identify differentially expressed genes. Expression of mRNA was compared between adult Lewis and Fischer 344 (F344) rats, adult and postnatal day 6 (d6) F344, and adult F344 treated with haloperidol or control vehicle. These groups were chosen because each highlights a particular aspect of schizophrenia: differences in strain vulnerability to behavioral analogs of psychosis; factors that may relate to disease onset in relation to CNS development; and improvement of symptoms by haloperidol. The 14-3-3 gene family, as represented by 14-3-3gamma and 14-3-3zeta isoforms in the SSH study, and SNAP-25 were among the candidate genes. Genetic association between schizophrenia and the 14-3-3eta gene, positioned close to a genomic locus implicated in schizophrenia, and SNAP-25 genes was analyzed in 168 schizophrenia probands and their families. These findings address three different genes in the 14-3-3 family. We find a significant association with schizophrenia for two polymorphisms in the 14-3-3eta gene: a 7 bp variable number of tandem repeats in the 5' noncoding region (P=0.036, 1 df), and a 3' untranslated region SNP (753G/A) that is an RFLP visualized with Ava II (P=0.028). There was no significant genetic association with SNAP-25. The candidate genes identified may be of functional importance in the etiology, pathophysiology or treatment response of schizophrenia or psychotic symptoms. This is to our knowledge the first report of a significant association between the 14-3-3eta-chain gene and schizophrenia in a family-based sample, strengthening prior association reports in case-control studies and microarray gene expression studies.

Asunto(s)

Ligamiento Genético , Esquizofrenia/genética , Tirosina 3-Monooxigenasa/genética , Proteínas 14-3-3 , Animales , Modelos Animales de Enfermedad , Femenino , Lóbulo Frontal/fisiopatología , Genotipo , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , Embarazo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Esquizofrenia/fisiopatología , Proteína 25 Asociada a Sinaptosomas , Lóbulo Temporal/fisiopatología