Cognitive Biases Questionnaire for Psychosis (CBQp): Spanish Validation and Relationship With Cognitive Insight in Psychotic Patients.

Introduction: Cognitive biases are key factors in the development and persistence of delusions in psychosis. The Cognitive Biases Questionnaire for Psychosis (CBQp) is a new self-reported questionnaire of 30 relevant situations to evaluate five types of cognitive biases in psychosis. In the context of the validation of the Spanish version of the CBQp, our objectives were to (1) analyze the factorial structure of the questionnaire with a confirmatory factor analysis (CFA), (2) relate cognitive biases with a widely used scale in the field of delusion cognitive therapies for assessing metacognition, specifically, Beck's Cognitive Insight Scale (BCIS) (1), and, finally, (3) associate cognitive biases with delusional experiences, evaluated with the Peters Delusions Inventory (PDI) (2). Materials and Methods: An authorized Spanish version of the CBQp, by a translation and back-translation procedure, was obtained. A sample of 171 patients with different diagnoses of psychoses was included. A CFA was used to test three different construct models. Associations between CBQp biases, the BCIS, and the PDI were made by correlation and mean differences. Comparisons of the CBQp scores between a control group and patients with psychosis were analyzed. Results: The CFA showed comparative fit index (CFI) values of 0.94 and 0.95 for the models with one, two, and five factors, with root mean square error of approximation values of 0.031 and 0.029. The CBQp reliability was 0.87. Associations between cognitive biases, self-certainty, and cognitive insight subscales of the BCIS were found. Similarly, associations between total punctuation, conviction, distress, and concern subscales of the PDI were also found. When compared with the group of healthy subjects, patients with psychoses scored significantly higher in several cognitive biases. Conclusion: Given the correlation between biases, a one-factor model might be more appropriate to explain the scale's underlying construct. Biases were associated with a greater frequency of delusions, distress, conviction, and concern as well as worse cognitive insight in patients with psychosis.

Upper thoracic spine fracture associated with fracture of the sternum / Fratura da parte superior da coluna torácica associada à fratura do esterno / Fractura de columna torácica alta asociada a fractura del esternón

ABSTRACT Objectives: The objectives of this presentation are to analyze the kinematics that causes this association, describe the impact of the injury, and evaluate the treatment performed Methods: Three cases are analyzed by quantifying the displacement and angulation of the sternum, the characteristics of the spinal injury and deformity, treatment, and complications Results: The mechanism that causes the injury is flexion-distraction, the component of the vertebral body presented is type A, and the most affected region was T5. Two patients had neurological picture E. Sternum injury was caused by direct trauma Conclusion: The association of these was observed in patients who have suffered from high-energy trauma in a car accident. There was no relationship between the angulation of the sternum and its displacement to the degree of kyphosis and displacement of the thoracic spine. It is important to carry out good radiographic studies that include the sternum when there is suspicion of this relationship.

RESUMO Objetivos: Os objetivos desta apresentação são analisar a cinemática que causa essa associação, descrever o impacto da lesão e avaliar o tratamento realizado. Métodos:: São analisados três casos, quantificando o deslocamento e a angulação do esterno e as características da lesão na coluna vertebral e deformidade, o tratamento e as complicações. Resultados: O mecanismo que provoca a lesão é a flexão-distração, o componente do corpo vertebral apresentado é de tipo A e a região mais afetada foi T5. Dois pacientes tinham quadro neurológico E. A lesão esterno foi causada por trauma direto. Conclusão: A associação destes foi observada em pacientes que sofreram trauma de alta energia em acidente automobilístico. Não encontramos relação entre a angulação do esterno e seu deslocamento com o grau de cifose ou deslocamento da coluna torácica. É importante realizar bons estudos radiográficos que incluam o esterno quando houver suspeita dessa relação.

RESUMEN Objetivos: Los objetivos de esta presentación son analizar la cinemática que ocasiona esta asociación, describir la repercusión de la lesión y evaluar el tratamiento realizado. Métodos: Se analizan tres casos, cuantificando desplazamiento y angulación del esternón y las características de la lesión vertebral y deformidad, el tratamiento y las complicaciones. Resultados:: El mecanismo que provoca la lesión es flexo-distracción, el componente del cuerpo vertebral presentado es de tipo A y la región más afectada fue T5. Dos pacientes tenían cuadro neurológico E. La lesión del esternón se debió a trauma directo. Conclusión: La asociación de estas se vio en pacientes que habían sufrido trauma de alta energía durante un accidente automovilístico. No encontramos relación entre la angulación del esternón y su desplazamiento con el grado de cifosis o desplazamiento en la columna torácica. Es importante realizar buenos estudios radiográficos que incluyan el esternón al sospechar esta relación.

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia.

It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia.

Initial validation of the Spanish childhood trauma questionnaire-short form: factor structure, reliability and association with parenting.

The present study examines the internal consistency and factor structure of the Spanish version of the Childhood Trauma Questionnaire-Short Form (CTQ-SF) and the association between the CTQ-SF subscales and parenting style. Cronbach's α and confirmatory factor analyses (CFA) were performed in a female clinical sample (n = 185). Kendall's ι correlations were calculated between the maltreatment and parenting scales in a subsample of 109 patients. The Spanish CTQ-SF showed adequate psychometric properties and a good fit of the 5-factor structure. The neglect and abuse scales were negatively associated with parental care and positively associated with overprotection scales. The results of this study provide initial support for the reliability and validity of the Spanish CTQ-SF.

New evidence for the involvement of mitochondrial inheritance in schizophrenia: results from a cross-sectional study evaluating the risk of illness in relatives of schizophrenia patients.

OBJECTIVE: One of the hypotheses about the genetic factors that contribute to schizophrenia involves mitochondrial DNA (mtDNA), an approximately 16,569-base pair molecule inherited only from the mother. If this hypothesis were true, one would expect a higher frequency of schizophrenia among matrilineal relatives who share mtDNA with a schizophrenia patient than among relatives who do not. This article reports the risk of presenting with schizophrenia, other psychiatric disorders, and conditions related to mitochondrial disorders in relatives who share mtDNA with a schizophrenia patient versus those who do not. METHOD: We interviewed 100 schizophrenia patients (DSM-IV criteria) and 147 of their first-degree relatives from November 2007 to November 2009 to collect clinical data from patients and from both sides of each patient's pedigree. The study was conducted at of a psychiatric teaching hospital in Reus, Spain. Contingency tables were established, and odds ratios were calculated to estimate relative risk. RESULTS: Relatives who shared mtDNA with a schizophrenia patient had a higher risk of presenting with schizophrenia than those who did not share mtDNA (odds ratio [OR] = 3.05; 95% CI, 1.65-5.72; P < .001). Female but not male relatives who shared mtDNA with a schizophrenia patient also had a higher risk of unipolar depression (OR =10.19; 95% CI, 4.07-32.80; P < .001), panic attack (OR = 15.52; 95% CI, 2.41-643.6; P < .001), and other anxiety disorders (OR = 4.14; 95% CI, 1.84-9.71; P < .001). Some conditions frequently associated with mitochondrial disorders were also more frequent among female relatives who shared mtDNA with a schizophrenia patient than among those who did not. CONCLUSIONS: The results of this study support the hypothesis that mtDNA may be involved in schizophrenia. In females, mtDNA could also be involved in the development of other psychiatric and nonpsychiatric conditions. Further studies are needed to confirm the role of mtDNA in psychiatric disorders.

No evidence that major mtDNA European haplogroups confer risk to schizophrenia.

Previous studies suggest that genetic factors could be involved in mitochondrial dysfunction observed in schizophrenia (SZ), some of them claiming a role of mtDNA common variants (mtSNPs) and/or haplogroups (hgs) in developing this disorder. These studies, however, have mainly been undertaken on relatively small cohorts of patients and control individuals and most have not yet been replicated. To further analyze the role of mtSNPs in SZ risk, we have carried out the largest genotyping effort to date using two Spanish case-control samples comprising a total of 942 schizophrenic patients and 1,231 unrelated controls: 454 patients and 616 controls from Santiago de Compostela (Galicia) and 488 patients and 615 controls from Reus (Catalonia). A set of 25 mtSNPs representing main branches of the European mtDNA phylogeny were genotyped in the Galician cohort and a subset of 16 out of these 25 mtSNPs was genotyped in the Catalan cohort. These 16 common variants characterize the most common European branches of the mtDNA phylogeny. We did not observe any positive association of mtSNPs and hgs with SZ. We discuss several deficiencies of previous studies that might explain the false positive nature of previous findings, including the confounding effect of population sub-structure and deficient statistical methodologies. It is unlikely that mtSNPs defining the most common European mtDNA haplogroups are related to SZ.

Spanish adaptation of the Beck Cognitive Insight Scale (BCIS) for schizophrenia.

INTRODUCTION: The Beck Cognitive Insight Scale has been designed to evaluate the cognitive insight capacity, that is to say, the practice of self-reflectiveness as a meta-cognitive mechanism for examining and analysing the disorder's symptoms, it also permits a continuous re-evaluation of inadequate interpretations. METHODOLOGY: The aim of this study is to examine the psychometric properties, the dimensional structure and the internal validity of the Spanish version of Beck's Cognitive Scale of Insight (BCIS). In this paper we also analyse its relation with the Positive and Negative Symptoms Scale (PANSS). The Cognitive Insight Scale was translated and adapted to Spanish with 129 in- and out-schizophrenic patients. RESULTS: Principal component analysis showed a two-factor structure that was similar to the original one, recognizable as self-reflectiveness (R) and self-certainty (C) with similar reliability as the American version. Self-reflectiveness and the R-C index correlated with loss of insight of the PANSS scale. In general, BCIS showed significant associations with the PANSS subscales. Out patients scored self-reflectiveness and R-C index signicantly higher than in-patients and lower in self-certainty. CONCLUSION: Psychometric properties obtained with the adapted Spanish version of BCIS guarantee the adequate evaluation of cognitive insight.

Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia.

BACKGROUND: Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). METHODS: We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. RESULTS: The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p < .01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10(-6), allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. CONCLUSIONS: Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

Increased morning adrenocorticotrophin hormone (ACTH) levels in women with postpartum thoughts of harming the infant.

INTRODUCTION: Some postpartum women experience intrusive thoughts of harming the infant. The hypothalamic-pituitary-adrenal (HPA) axis, which has been linked to postpartum depression, may play a role in the aetiology of postpartum thoughts of harming the infant. We aimed to study whether HPA axis hormones measured early postpartum are related to postpartum intrusive thoughts. METHOD: 132 women who delivered a child at a university hospital participated in a follow-up study with visits at 2-3 days postpartum and 8th week postpartum. Participants were assessed for trait anxiety, social support, peripartum or postpartum anxiety or depression, stressful life events and obstetric variables including perinatal complications and lactation. Postpartum thoughts of harming the infant were assessed with a semi-structured interview. Serum cortisol, and plasma CRH and ACTH levels were measured within 48 h postpartum at 8-9 AM. A logistic regression was performed to explore the relationship between clinical variables, hormonal measures and postpartum intrusive thoughts. RESULTS: Patients with postpartum thoughts of harming the infant had, when compared to those women without intrusive thoughts, higher ACTH levels (7.59 pmol/L vs 5.09 pmol/L, p<0.05) without significant differences in CRH or cortisol levels. In the logistic regression analysis, adjusted for breast-feeding and psychopathological status, only ln ACTH was associated with the presence of postpartum thoughts of harming the infant (OR=5.2, CI 95% 1.2-22.6, p=0.029). No other clinical variables were associated with postpartum intrusive thoughts. CONCLUSIONS: Our study suggests that a dysregulation of the hypothalamic-pituitary-adrenal axis may play a role in the aetiology of postpartum thoughts of harming the infant.

Resequencing and association analysis of arylalkylamine N-acetyltransferase (AANAT) gene and its contribution to major depression susceptibility.

Circadian rhythms disruptions, including abnormalities of circadian phase position and melatonin secretion, have been described in major depression (MD). Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme of the melatonin pathway involved in circadian oscillations of melatonin levels. We assessed the contribution of AANAT gene variability to susceptibility to MD considering common and rare genetic variations through a sequential sequencing and single nucleotide polymorphism (SNP)-based genotyping approach in a sample of 445 unrelated patients with MD (257 unipolar MD, 188 bipolar depression) and 440 community-based screened control subjects. We identified 17 sequence changes, thirteen of which represented novel sequence variations. We did not observe an over-representation of patients carrying rare variants compared with the healthy controls. Common variants (MAF > 2%) were included in a case-control association analysis that showed significant association after multiple testing correction of two SNPs located in the promoter region of AANAT with MD: rs3760138 (P = 0.00006) and rs4238989 (P = 0.005). Multimarker analysis found significant associations between two three-marker protective haplotypes and a susceptibility three-marker haplotype containing the rare alleles of rs3760138-rs4238989-rs8150 and MD. We present evidence of the association of genetic variability in the AANAT gene with susceptibility to MD. Our results support the hypothesis that the melatonin-signaling pathway and circadian clock mechanisms may contribute to the pathophysiology of MD.

Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.

Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3' near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.

A common haplotype of DRD3 affected by recent positive selection is associated with protection from schizophrenia.

The number and frequency of susceptibility alleles at loci associated to most psychiatric disorders is largely unknown, in spite of its relevance for the design of studies aiming to find these alleles. Both, common polymorphisms and rare mutations may contribute to the genetic susceptibility to complex psychiatric disorders, being the relative relevance of each type of variation currently under debate. Here, we confirmed the existence of a common protective haplotype against schizophrenia at the dopamine D(3) receptor (DRD3) gene, by replication and pooled analysis with previous data (Mantel-Haenszel chi(2) P value = 0.00227; OR = 0.79, 95% CI 0.68-0.92, based on 794 cases and 1,078 controls from three independent populations of European origin). This protective haplotype is at very low frequency in Sub-Saharan Africans (median 0.06) and at intermediate frequencies in other populations (median 0.25). We also revealed, by examining the patterns of linkage disequilibrium around this gene, that the protective haplotype has reached high frequency in non-African populations due to selection acting, most probably, on a linked functional polymorphism, the non-synonymous single nucleotide polymorphism Ser9Gly (rs6280), also at DRD3. Thus, this finding shows that the natural selection may play a role in the existence of common alleles conferring different susceptibility to schizophrenia.

Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

Adaptation and validation of the Spanish version of the Strauss and Carpenter Prognostic Scale for Schizophrenia.

INTRODUCTION: The aim of this study was to validate the Spanish version of the Strauss and Carpenter Prognostic Scale for Schizophrenia (Strauss and Carpenter, 1977). METHOD: We performed a multicenter, longitudinal, descriptive study. Forward and backtranslation of the original scale was performed. The sample was composed of persons diagnosed with schizophrenia aged between 18 and 65 years. We calculated interrater reliability, construct validity according to the Global Assessment Scale (GAS), Satisfaction with Life Domains Scale (SLDS), the Global Clinical Impression-Schizophrenia (GCI) scale, The World Health. Organization Short Disability Assessment Schedule (WHO-DAS) and the Positive and Negative Syndrome Scale (PANSS), and predictive validity at the 1-year follow-up using three criterion measures of the GCI, WHO-DAS and GAS scales. RESULTS: The internal consistency coefficient (Cronbach's alpha) was 0.70. The intraclass correlation coefficient ranged from 0.54 to 0.99, except for item 5 (resources for the current treatment), which was -0.13. The correlation between the distinct scales (measuring construct validity) was significant, with a p-value of < 0.01, except for the SLDS, which showed a higher p-value (p<0.05). The Strauss-Carpenter score correlated with all three scores at 1 year (GCI, GAS and WHO-DAS) with an alpha of less than 0.01, showing good predictive validity. CONCLUSIONS: The Spanish adaptation of the Strauss and Carpenter prognostic scale is reliable and valid and allows a more severe disease course to be predicted.

Structure of personality pathology in normal and clinical samples: Spanish validation of the DAPP-BQ.

Given that the DSM taxonomy of personality disorders is flawed by severe classificatory problems, the development of alternative classificatory systems, such as the Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ), has now become a priority. This study examined the internal consistency, second-order factor structure, and criterion validity of a Spanish translation of the DAPP-BQ in two samples: subjects with personality disorder (n = 155) and subjects from the general population (n = 300). Alpha coefficients ranged satisfactorily from .75 to .93. Four second-order factors of Emotional Dysregulation, Dissocial Behavior, Inhibitedness, and Compulsivity were obtained, which were replicable between samples and identical to those reported in the literature. Finally, disordered subjects scored significantly higher than normal subjects on 17 of the 18 DAPP-BQ traits. Some pending issues in the construction of an alternative taxonomy of personality disorders are discussed.

Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia.

Relationships between gender, age-of-onset of schizophrenia and reproductive age strongly suggest a key role for gonadal hormones, and more specifically for estrogens, in the etiology of the illness. Also, estrogens act as neural growth and trophic factors influencing neuron and glial cells in many areas of the central nervous system. Therefore, we investigated the association between schizophrenia and 4 genes related to estrogen metabolism. These genes are ESR1 (estrogen receptor 1), ESR2 (estrogen receptor 2), APOE (apolipoprotein E) and COMT (catechol-O-methyltransferase). The expression of APOE and COMT, which contain estrogen response elements, have been demonstrated to be regulated by the estrogen receptors. In this current association study, we examined 59 single nucleotide polymorphisms (SNPs) located in the ESR1 (26), ESR2 (14), APOE (7) and COMT (12) loci. Allele frequencies were evaluated in the schizophrenia (n=585)-control (n=615) sample and no association was found with any of the four genes. In conclusion, our data suggest that the four analyzed genes do not play an important role in susceptibility to schizophrenia.

Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction.

Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited.

M129V variation in the prion protein gene and psychotic disorders: relationship to neuropsychological and psychopathological measures.

The methionine/valine polymorphism at position 129 in the prion protein gene, PRNP M129V, is a known risk factor for Creutzfeldt-Jakob disease (CJD). Psychiatric manifestations including psychosis are common in the early phase of CJD and it has therefore been hypothesized that the prion protein could be involved in psychotic disorders. Moreover, among the various hypothesized functions of the prion protein, a role in synaptic activity has been described. We have studied the PRNP M129V variant with regard to psychotic disorders from two perspectives: first as a genetic risk factor and second as a genetic factor influencing phenotypic variation. A case-control study of 482 psychotic patients and 502 controls indicated that differences between patients and controls were not present in genotype distributions or allele frequencies. We also studied the influence of this variant in psychopathological symptomatology and neuropsychological performance in a subgroup of 159 psychotic patients. In our sample, patients homozygous for valine at this position presented less severe scores in the general psychopathological subscale (p=0.003) and in the sum of the total items (p=0.007) of the Positive and Negative Syndrome Scale (PANSS). Also, homozygote VV patients presented better scores in most neuropsychological tests, the most significant result of which was for delayed visual memory (p=0.021). In summary, our results do not support the hypothesis that M129V is a susceptibility factor for psychotic disorders. However, it could influence their phenotypic variation at the psychopathological and neuropsychological level. Independent replications are needed to confirm that being homozygotic for valine at PRNP M129V position is associated with better psychopathological and neuropsychological scores in psychotic disorders.

New variants in the mitochondrial genomes of schizophrenic patients.

The impaired mitochondrial function hypothesis in schizophrenia is based on evidence of altered brain metabolism, morphology, biochemistry and gene expression. Mitochondria have their own genome, which is needed to synthesize some of the subunits of the respiratory chain enzymes. Mitochondrial DNA (mtDNA) is maternally inherited and we observed an excess of maternal transmission of schizophrenia in a set of parent-offspring affected pairs. We therefore hypothesized that mutations in the mtDNA may contribute to the complex genetic basis of schizophrenia. The entire mtDNA of six schizophrenic patients with an apparent maternal transmission of the disease was sequenced and compared to the reference sequence. We have identified 50 variants and among these six have not been previously reported. Three of them were missense variants: MTCO2 7750C>A, MTATP6 8857G>A and MTND4 12096T>A. These were maternally inherited because they were also present in the mtDNA of their respective schizophrenic mothers and none of them were found in 95 control individuals. The MTND4 12096T>A (Leu446His) is a heteroplasmic variant present in five of the six mother-offspring patient pairs that triggers a non-conservative substitution in the ND4 subunit of complex I. Sequence alignment of 110 ND4 peptides from all eukaryotic kingdoms shows that only hydrophobic amino acids are found in this position. Moreover, leucine was conserved or substituted by an isoleucine in all mammalian species. This indicates that the presence of histidine could affect complex I activity in patients with schizophrenia.

Further evidence that hyperhomocysteinemia and methylenetetrahydrofolate reductase C677T and A1289C polymorphisms are not risk factors for schizophrenia.

It has been suggested that total plasma homocysteine (tHcy) concentrations and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms are risk factors for schizophrenia. We conducted a case-control study to investigate whether tHcy levels and MTHFR C677T and A1298C variants are associated with schizophrenia, giving special consideration to confounding factors. Logistic regression analysis showed that neither tHcy nor MTHFR polymorphisms were associated with schizophrenia. Homozygosity for MTHFR C677T was associated with higher tHcy concentrations in control and schizophrenia groups (P<0.01), which was mainly driven by the male group. The A1298C variant did not show any association with tHcy concentrations. In conclusion, these results do not confirm an independent relationship of tHcy and MTHFR genotype with risk of schizophrenia.