RESUMEN
Schizophrenic psychoses are the result of a multifactorial process in which not only environmental influences but also genetic factors play an important role. These factors are based on a complex mode of inheritance that involves a large number of genetic variants. In the last three decades, biological psychiatric research has focused closely on molecular genetic aspects of the hereditary basis of schizophrenic psychoses. In particular, international consortia are combining cohorts from individual researchers, creating continuously increasing sample sizes and thus increased statistical power. As part of the Psychiatric Genomics Consortium (PGC), genome-wide association studies with tens of thousands of patients and controls have for the first time found robustly replicable markers for schizophrenic psychoses. Through intensive phenotyping, first approaches to a transdiagnostic clinical reclassification of severe mental illnesses have been established in the longitudinal PsyCourse study of the UMG Göttingen and the LMU Munich, allowing new biologically validated disease subgroups with prognostic value to be identified. For the first time environmental factors could even be examined in an African cohort that contribute to the development of the psychosis. In the coming years, the enormous technical progress in the area of genomic high-throughput technologies (next-generation sequencing) is expected to provide new knowledge not only about the influence of frequently occurring single nucleotide polymorphisms but also about rare variants. For the successful use of this technological revolution an exchange of data between research groups is essential.
Asunto(s)
Trastornos Psicóticos , Esquizofrenia , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Difusión de la Información , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genéticaRESUMEN
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.
Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Ritmo Circadiano/genética , Compuestos de Litio/uso terapéutico , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Adulto , Trastorno Bipolar/metabolismo , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas de Choque Térmico/genética , Humanos , Masculino , Persona de Mediana Edad , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genéticaRESUMEN
Large-scale collaborative research will be a hallmark of future psychiatric genetic research. Ideally, both academic and non-academic institutions should be able to participate in such collaborations to allow for the establishment of very large samples in a straightforward manner. Any such endeavor requires an easy-to-implement information technology (IT) framework. Here we present the requirements for a centralized framework and describe how they can be met through a modular IT toolbox.
Asunto(s)
Psiquiatría Biológica/métodos , Psiquiatría Biológica/tendencias , Conducta Cooperativa , Investigación Genética , Informática Médica/métodos , Informática Médica/tendencias , Humanos , Modelos Organizacionales , Programas InformáticosRESUMEN
Stress has been reported to regulate adrenergic receptors but it is not known whether it has an impact on the alpha-2 adrenoceptor subtype B that is strongly expressed in distinct nuclei of the thalamus. So far little is known about effects of stress on the thalamus. Using the chronic psychosocial stress paradigm in male tree shrews, we analyzed alpha-2B adrenoceptor expression in the paraventricular and the anteroventral nucleus of the thalamus after a six-week period of daily social stress and after a 10-day post-stress recovery period. In situ hybridization with a specific alpha-2B adrenoceptor probe was performed to quantify receptor gene expression in single neurons, and receptor binding was determined by in vitro receptor autoradiography using the radioligand [3H]RX821002. To determine the stress level in the animals, we measured urinary cortisol excretion and body weight. In the neurons of the paraventricular thalamic nucleus, expression of the alpha-2B adrenoceptor transcript was increased after both the six-week chronic-stress period and the post-stress recovery period. Combination of in situ hybridization and immunocytochemistry revealed expression of alpha-2B adrenoceptor transcript in neurons that were stained with an antibody against glutamate but not in neurons immunoreactive for GABA. Alpha-2 adrenoceptor radioligand binding was also increased after both time periods in the paraventricular thalamic nucleus. No significant effects of stress and recovery were observed in the anteroventral thalamic nucleus. Urinary cortisol excretion was increased during the stress period but normalized thereafter. Body weight was reduced during weeks 1 to 3 of stress and then normalized. These data show that long-term chronic psychosocial stress has an impact on alpha-2B adrenoceptor expression in the thalamus and that the effect persists throughout a post-stress recovery period though activity of the hypothalamic pituitary adrenal axis normalizes after stress. Upregulation of the receptor probably alters neurotransmission in the paraventricular thalamic nucleus and may thus influence information transfer to limbic and cortical brain areas.