[Show abstract][Hide abstract] ABSTRACT: Background:
Glutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients' cognitive performance.
The sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses.
The haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results.
Our findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.
Full-text · Article · Feb 2016 · European Psychiatry
[Show abstract][Hide abstract] ABSTRACT: The hippocampus is a key modulator of stress responses underlying depressive behavior. While FKBP5 has been found associated with a large number of stress-related outcomes and hippocampal features, its potential role in modifying the hippocampal communication transfer mechanisms with other brain regions remains largely unexplored. The putative genetic or environmental roots of the association between depression and structural connectivity alterations of the hippocampus were evaluated combining diffusion weighted imaging with both a quantitative genetics approach and molecular information on the rs1360780 single nucleotide polymorphism, in a sample of 54 informative monozygotic twins (27 pairs). Three main results were derived from the present analyses. First, graph-theoretical measures of hippocampal connectivity were altered in depression. Specifically, decreased connectivity strength and increased network centrality of the right hippocampus were found in depressed individuals. Second, these hippocampal alterations are potentially driven by familial factors (genes plus shared environment). Third, there is an additive interaction effect between FKBP5’s rs1360780 variant and the graph-theoretical metrics of hippocampal connectivity to influence depression risk. Our data reveals alterations of the communication patterns between the hippocampus and the rest of the brain in depression, effects potentially driven by overall familial factors (genes plus shared twin environment) and modified by the FKBP5 gene.
No preview · Article · Jan 2016 · Brain Imaging and Behavior
[Show abstract][Hide abstract] ABSTRACT: Los síntomas básicos consisten en sutiles molestias subclínicas, experimentadas subjetivamente por el paciente, principalmente referidas a la volición, la afectividad, el pensamiento y lenguaje, la percepción, la memoria, la acción motora, las funciones vegetativas centrales, el control de procesos cognitivos auomáticos y la tolerancia al estrés. Descritos inicialmente por Huber, desde una aproximación fenomenológica, forman parte de las manifestaciones más precoces de la esquizofrenia, a lo largo de cuyo curso pueden adquirir diferente evolución. Su presentación durante la fase prodrómica de la enfermedad, para cuya evaluación han sido desarrollados diferentes instrumentos, constituye (junto con los criterios ultra-high risk) una de las 2 principales aproximaciones para su caracterización, lo que permite definir estados clínicos de riesgo para el desarrollo de psicosis. En la presente revisión se ofrece una visión actualizada del concepto de síntomas básicos, subrayando su potencial valor a la hora de establecer correlatos neurobiológicos de interés en la investigación etiopatogénica.
No preview · Article · Jan 2016 · Revista de Psiquiatría Biológica y Salud Mental
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Phenotype definition of psychotic disorders has a strong impact on the degree of familial aggregation. Nevertheless, the extent to which distinct classification systems affect familial aggregation (ie, familiality) remains an open question. This study was aimed at examining the familiality associated with 4 nosologic systems of psychotic disorders (DSM-IV, ICD-10, Leonhard's classification and a data-driven approach) and their constituting diagnoses in a sample of multiplex families with psychotic disorders.
Participants were probands with a psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The sample was made of 441 families comprising 2703 individuals, of whom 1094 were affected and 1709 unaffected.
The Leonhard classification system had the highest familiality (h (2) = 0.64), followed by the empirical (h (2) = 0.55), DSM-IV (h (2) = 0.50), and ICD-10 (h (2) = 0.48). Familiality estimates for individual diagnoses varied considerably (h (2) = 0.25-0.79). Regarding schizophrenia diagnoses, Leonhard's systematic schizophrenia (h (2) = 0.78) had the highest familiality, followed by latent class core schizophrenia (h (2) = 0.74), DSM-IV schizophrenia (h (2) = 0.48), and ICD-10 schizophrenia (h (2) = 0.41). Psychotic mood disorders showed substantial familiality across nosologic systems (h (2) = 0.60-0.77). Domains of psychopathology other than reality-distortion symptoms showed moderate familiality irrespective of diagnosis (h (2) = 0.22-0.52) with the deficit syndrome of schizophrenia showing the highest familiality (h (2) = 0.66).
While affective psychoses showed relatively high familiality estimates across classification schemes, those of nonaffective psychoses varied markedly as a function of the diagnostic scheme with a narrow schizophrenia phenotype maximizing its familial aggregation. Leonhard's classification of psychotic disorders may be better suited for molecular genetic studies than the official diagnostic systems.
No preview · Article · Dec 2015 · Schizophrenia Bulletin
[Show abstract][Hide abstract] ABSTRACT: Objectives Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results The frequency of the haplotype C-C (rs645649–rs582262) was significantly increased in patients compared to controls (P = 0.0043), while the haplotype T-C-C-T-C-A (rs3763180–rs10484320–rs4960155–rs9379002–rs9405890–rs1475157) was more frequent in controls (P = 3.1 × 10−5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P = 0.005). Conclusions Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF.
No preview · Article · Dec 2015 · The World Journal of Biological Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across five consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05-0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.
No preview · Article · Sep 2015 · Epigenetics: official journal of the DNA Methylation Society
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia patients typically present a widespread bilateral cortical thinning from the early stages of the illness. However, there is controversy whether this reduction in cortical thickness (CT) is static or progressive over the evolution of the disorder. Disrupted-in-Schizophrenia 1 (DISC1) is one of the main candidates genes for schizophrenia, as it has been found associated to the illness, and to several endophenotypes of the disorder including structural brain differences. This gene is known to be involved in neurodevelopment and brain maturation processes. We therefore hypothesized that variations in this gene modulate different progressions of CT in psychosis. Seventy-nine Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs6675281 (Leu607Phe) and rs821616 (Ser704Cys) SNPs of the DISC1 gene. Brain MRIs were carried out at baseline and 3 years after initiating the treatment. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. Patients homozygous for the Leu allele of the rs6675281 SNP had a significant (p < 0.05) descend in CT over the 3-years period, while those carrying the Phe allele presented an increase in CT. When combining the two SNPs we found a synergic effect on CT progression, presenting those patients homozygous for Leu607 +Ser704 a more pronounced cortical thinning. In conclusion, DISC1 gene variations may modulate the longitudinal changes in cortical thickness in patients suffering from a first episode of non-affective psychosis.
No preview · Article · Jul 2015 · Brain Imaging and Behavior
[Show abstract][Hide abstract] ABSTRACT: The main aim of the present research was to study the prospective relationships of the five-factor model of personality and the internalizing and externalizing suprafactors of psychopathology. A sample of 323 young adults completed the NEO-FFI at Time 1 and different scales of symptoms 5 years later. Neuroti- cism prospectively predicted the internalizing factor, while extraversion, low agreeableness and low con- scientiousness predicted the externalizing factor. We found additional paths between introversion and social phobia symptoms, and between low agreeableness and psychopathy symptoms. These relation- ships remained significant, even when controlling for previous symptoms, except for extraversion. Gen- der had no moderation effect on the interrelationship between personality and psychopathology factors. The present study extends previous research about personality and psychopathology, and suggests differ- ent ways in which they can be related.
Full-text · Article · Jun 2015 · Personality and Individual Differences
[Show abstract][Hide abstract] ABSTRACT: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles.
We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects.
Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders.
The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.
[Show abstract][Hide abstract] ABSTRACT: Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.
[Show abstract][Hide abstract] ABSTRACT: Background
Few studies have analyzed the course of neurocognition in treated children and adolescents with early-onset bipolar disorder (EOBD) and shown improvements in attention, working memory, and verbal memory after treatment. The aim of this study was to determine the progress over two years in neuropsychological performance of a sample of medicated adolescents with EOBD compared to healthy controls (HC).
Twenty adolescents, diagnosed in clinical setting as DSM-IV bipolar disorder, treated for two years, euthymic, and 20 gender and age-matched HC were assessed at two moments in reasoning, verbal and visual memory, working memory, speed, visual-motor skills and executive function. Multivariate analyses of variance was carried out to analyze the differences between groups over time, and to monitor the influence of psychotic symptoms and type of mood-stabilizer.
The entire sample improved on verbal and visual memory tests (verbal recall p<0.01; visual recall p<0.001). Moreover, patients improved more than controls in verbal reasoning (p<0.01), working memory (p<0.01), processing speed (p<0.01) and visual-motor skills (p<0.001). Psychotic symptoms and treatment with lithium were associated with poorer development in executive control tasks.
Sample size was small and groups were re-evaluated in slight different follow-up periods. Doses of antipsychotics drugs over time were not controlled.
Processing speed and visual-motor skills in the EOBD group normalized during follow-up. Executive functioning, working memory, and verbal and visual memory remained impaired in patients versus controls. The knowledge of cognitive deficits due to normal course of illness or to drug effects allows better therapeutic strategies.
No preview · Article · Feb 2015 · Journal of Affective Disorders