Manuel Arrojo

Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: New data and meta-analysis

Catechol-O-methyltransferase (COMT) has been largely studied in relation to schizophrenia susceptibility. Most studies focused on the functional single nucleotide polymorphism (SNP) rs4680 that causes a substitution of Val by Met at codon 158 of the COMT protein. Recent meta-analyses do not support an association between allelic variants at rs4680 and schizophrenia. However, the putative role of overdominance has not been tested in meta-analyses, despite its biological plausibility. In this work, we tested the overdominant model in two Spanish samples (from Valencia and Santiago de Compostela), representing a total of 762 schizophrenic patients and 1042 controls, and performed a meta-analysis of the available studies under this model. A total of 51 studies comprising 13,894 schizophrenic patients and 16,087 controls were included in the meta-analysis, that revealed a small but significant protective effect for heterozygosity at rs4680 (pooled OR=0.947, P=0.023). Post-hoc analysis on southwestern European samples suggested a stronger effect in these populations (pooled OR=0.813, P=0.0009). Thus, the COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine (DA) signalling may be risk factors. This effect can be modulated by genetic background.

Interaction between COMT haplotypes and cannabis in schizophrenia: A case-only study in two samples from Spain

Cannabis use is one of the environmental factors with more solid evidence contributing to schizophrenia risk, especially in genetically susceptible individuals. One of the genes that may interact with cannabis is COMT, although available data are scarce. Here, we present a case-only study of the putative COMT-cannabis interaction in schizophrenia. Two Spanish samples from Santiago de Compostela and Valencia were screened for cannabis use. One hundred and fifty five individuals from a total of 748 patients were identified as cannabis users. Five SNPs in COMT, defining three common functional haplotypes with different enzymatic activities, were genotyped and analyzed for association at the SNP, haplotype and genotype levels. An association was detected between cannabis use and low activity variants (P<0.01) in the joint analysis and results were consistent between the two samples. Schizophrenic subjects homozygous for the Met allele at rs4680 doubled the probability of lifetime prevalence of cannabis use in comparison to Val homozygous (Mantel-Haenszel OR=2.07, 95% CI: 1.27-3.26, P=0.0031, in the combined sample). These data are in contrast to those from Caspi et al. (Biol. Psychiatry 57 (2005)1117-1127) who found association between schizophrenia/schizophreniform disorder and homozygosity at the high activity Val variant of rs4680. The results of our study are discussed in the context of previous findings, suggesting the involvement of COMT polymorphisms in the association between cannabis use and schizophrenia as well as the existence of additional factors mediating this association. However, further research is needed to confirm the COMT-cannabis interaction.

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.

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.

Treated Incidence of Psychotic Disorders in the Multinational EU-GEI Study

Importance Psychotic disorders contribute significantly to the global disease burden, yet the latest international incidence study of psychotic disorders was conducted in the 1980s. Objectives To estimate the incidence of psychotic disorders using comparable methods across 17 catchment areas in 6 countries and to examine the variance between catchment areas by putative environmental risk factors. Design, Setting, and Participants An international multisite incidence study (the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions) was conducted from May 1, 2010, to April 1, 2015, among 2774 individuals from England (2 catchment areas), France (3 catchment areas), Italy (3 catchment areas), the Netherlands (2 catchment areas), Spain (6 catchment areas), and Brazil (1 catchment area) with a first episode of nonorganic psychotic disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20-F33) confirmed by the Operational Criteria Checklist. Denominator populations were estimated using official national statistics. Exposures Age, sex, and racial/ethnic minority status were treated as a priori confounders. Latitude, population density, percentage unemployment, owner-occupied housing, and single-person households were treated as catchment area–level exposures. Main Outcomes and Measures Incidence of nonorganic psychotic disorders (ICD-10 codes F20-F33), nonaffective psychoses (ICD-10 codes F20-F29), and affective psychoses (ICD-10 codes F30-F33) confirmed by the Operational Criteria Checklist. Results A total of 2774 patients (1196 women and 1578 men; median age, 30.5 years [interquartile range, 23.0-41.0 years]) with incident cases of psychotic disorders were identified during 12.9 million person-years at risk (crude incidence, 21.4 per 100 000 person-years; 95% CI, 19.4-23.4 per 100 000 person-years). A total of 2183 patients (78.7%) had nonaffective psychotic disorders. After direct standardization for age, sex, and racial/ethnic minority status, an 8-fold variation was seen in the incidence of all psychotic disorders, from 6.0 (95% CI, 3.5-8.6) per 100 000 person-years in Santiago, Spain, to 46.1 (95% CI, 37.3-55.0) per 100 000 person-years in Paris, France. Rates were elevated in racial/ethnic minority groups (incidence rate ratio, 1.6; 95% CI, 1.5-1.7), were highest for men 18 to 24 years of age, and were lower in catchment areas with more owner-occupied homes (incidence rate ratio, 0.8; 95% CI, 0.7-0.8). Similar patterns were observed for nonaffective psychoses; a lower incidence of affective psychoses was associated with higher area-level unemployment (incidence rate ratio, 0.3; 95% CI, 0.2-0.5). Conclusions and Relevance This study confirmed marked heterogeneity in risk for psychotic disorders by person and place, including higher rates in younger men, racial/ethnic minorities, and areas characterized by a lower percentage of owner-occupied houses.

Psychiatric presentation of Hashimoto's encephalopathy.

Introduction: Hashimotos encephalopathy is an unusual condition that is associated with Hashimotos thyroiditis. Myoclonus, epileptic seizures, dementia, and disturbances of consciousness are the most common features. Case report: We present an atypical case of Hashimotos encephalopathy in a 33-year-old woman who presented with several brief and acute psychotic episodes. After treatment with steroids, there was an improvement in the patients psychiatric symptoms and electroencephalogram, and antithyroglobulin antibody titers returned to normal levels. Conclusions: It is our opinion that Hashimotos encephalopathy should be considered in the differential diagnosis of atypical psychosis, especially because this is a treatable syndrome. This is particularly important in patients with a previous history of thyroid disease, despite current normal thyroid function. CT = computed tomography; EEG = electroencephalogram.

Role of DISC1 Interacting Proteins in Schizophrenia Risk from Genome‐Wide Analysis of Missense SNPs

A balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein–protein interactions involved in multiple developmental pathways within the brain. Gene set‐based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome‐wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome‐wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P‐value = 0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading‐edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.

Psychometric Properties of the Spanish Version of the Changes in Sexual Functioning Questionnaire Short‐Form (CSFQ‐14) in Patients with Severe Mental Disorders

INTRODUCTION Sexual dysfunction in patients with severe mental disorders is often underestimated or overlooked by psychiatrists. A brief and valid self-report instrument for assessing sexual functioning may well contribute to changing this situation. AIMS To validate the Short Form of the Changes in Sexual Functioning Questionnaire (CSFQ-14) in Spanish patients with severe mental disorders. METHODS Naturalistic, cross-sectional, multicenter, validation study. Eighty-nine patients with schizophrenia and 82 with bipolar disorder were evaluated using the CSFQ-14, the Visual Analogue Scale for Sexual Functioning Satisfaction (VAS-SFS), and the Clinical Global Impression-Severity scales for mental disorders (CGI-S) and for Sexual Dysfunction (CGI-SSD). MAIN OUTCOME MEASURES The 14-item Changes in Sexual Functioning Questionnaire. RESULTS Internal reliability (Cronbachs alpha) = 0.90. Construct validity = 3 principal components, of which the first, arousal-orgasm, explained 46.4% of the total variance. Convergent validity: Pearson correlation coefficients between CSFQ-14 and VAS-SFS = 0.33 (P < 0.01) and between CSFQ-14 and CGI-SDS = -0.71 (P < 0.01). Discriminant validity: The CSFQ-14 was able to discriminate among patients with no, mild, moderate, and severe sexual dysfunction according to CGI-SDS scores, both in males (P < 0.001) and females (P < 0.001). In males, the area under the curve (AUC) was 0.833 and a cutoff point of 49 provided a sensitivity of 92.9% and a specificity of 59.5%. In females, the AUC was 0.834 and a cutoff point of 43 provided a sensitivity of 91.9% and a specificity of 62.5%. CONCLUSION The Spanish version of the CSFQ-14 is a reliable and valid instrument for assessing sexual functioning in patients with severe mental disorders. As a brief, self-rated instrument, the CSFQ-14 scale seems to be appropriate for use in everyday clinical practice as a means of identifying and monitoring changes in sexual functioning.

Predictive factors of functional capacity and real-world functioning in patients with schizophrenia

PURPOSE This study was performed to identify the predictive factors of functional capacity assessed by the Spanish University of California Performance Skills Assessment (Sp-UPSA) and real-world functioning assessed by the Spanish Personal and Social Performance scale (PSP) in outpatients with schizophrenia. METHODS Naturalistic, 6-month follow-up, multicentre, validation study. Here, we report data on 139 patients with schizophrenia at their baseline visit. ASSESSMENT Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), Sp-UPSA and PSP. STATISTICS Pearsons correlation coefficient (r) was used to determine the relationships between variables, and multivariable stepwise linear regression analyses to identify predictive variables of Sp-UPSA and PSP total scores. RESULTS Functional capacity: scores on the PSP and PANSS-GP entered first and second at P<0.0001 and accounted for 21% of variance (R(2)=0.208, model df=2, F=15.724, P<0.0001). Real-world functioning: scores on the CGI-S (B=-5.406), PANSS-N (B=-0.657) and Sp-UPSA (B=0.230) entered first, second and third, and accounted for 51% of variance (model df=3, F=37.741, P<0.0001). CONCLUSION In patients with schizophrenia, functional capacity and real-world functioning are two related but different constructs. Each one predicts the other along with other factors; general psychopathology for functional capacity, and severity of the illness and negative symptoms for real-world functioning. These findings have important clinical implications: (1) both types of functioning should be assessed in patients with schizophrenia and (2) strategies for improving them should be different.

Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain

Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p=1.7×10(-4), Allelic odds ratio=1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p<0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis.