Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.

OBJECTIVE: Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. METHOD: We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. RESULTS: We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). CONCLUSION: The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.

[Analysis of polymorphism rs1051730 of CHRNA3 in patients with dual pathology in a Mexican population]. / Analisis del polimorfismo rs1051730 de CHRNA3 en pacientes con patologia dual en poblacion mexicana.

INTRODUCTION: Epidemiological studies have described a high comorbidity of substance use disorders with another psychiatric disorder, which has been called dual pathology. However, the aetiological mechanisms underlying this association are still not fully understood. AIM: To carry out a preliminary study of the effect of polymorphism rs1051730 of the gene group CHRNA5-CHRNA3-CHRNB4 through a case-control study. SUBJECTS AND METHODS: A total of 225 subjects were selected and divided into three groups: those diagnosed with bipolar disorder, those with nicotine dependence, and subjects without nicotine dependence or any other psychiatric disorder. Genotyping was performed by real-time polymerase chain reaction. Genetic association analysis was performed using chi-square tests and multivariate logistic regressions. RESULTS: On comparing allelic frequencies with the control group, we found that polymorphism rs1051730 was associated with nicotine dependence (p = 0.03), but not with bipolar disorder (p = 0.94). CONCLUSION: Variant rs1051730 was associated with nicotine dependence in the Mexican population and showed the same effect in dual pathology. However, further studies are recommended to obtain conclusive results.

TITLE: Analisis del polimorfismo rs1051730 de CHRNA3 en pacientes con patologia dual en poblacion mexicana.Introduccion. Estudios epidemiologicos han descrito una alta comorbilidad de los trastornos de uso de sustancias con otro trastorno psiquiatrico, al cual se le ha llamado patologia dual. Sin embargo, los mecanismos etiologicos de esta asociacion continuan siendo dificiles de entender. Objetivo. Realizar un estudio preliminar del efecto del polimorfismo rs1051730 del grupo de genes CHRNA5-CHRNA3-CHRNB4 a traves de un estudio de casos y controles. Sujetos y metodos. Se selecciono a un total de 225 sujetos, divididos en tres grupos: con diagnostico de trastorno bipolar, con dependencia a la nicotina y sujetos sin dependencia a la nicotina o cualquier otro trastorno psiquiatrico. La genotipificacion se realizo mediante reaccion en cadena de la polimerasa en tiempo real. El analisis de asociacion genetica se realizo mediante pruebas de chi cuadrado y regresiones logisticas multivariables. Resultados. Al comparar las frecuencias alelicas con el grupo control, encontramos que el polimorfismo rs1051730 se asocio con el grupo de dependencia a la nicotina (p = 0,03), pero no con el de trastorno bipolar (p = 0,94). Conclusion. La variante rs1051730 se asocio con dependencia a la nicotina en la poblacion mexicana y mostro el mismo efecto en la patologia dual. Sin embargo, se recomiendan estudios adicionales para tener resultados concluyentes.

Temperament and character in violent schizophrenic patients.

UNLABELLED: Preliminary evidence shows that personality traits are important in determining violent behavior in schizophrenia. As only some patients with schizophrenia show a greater risk for violence, this risk may therefore be considered as dynamic, varying as a function of the extent to which certain personality dimensions are present and the degree to which environmental events moderate or exacerbate their expression. OBJECTIVE: To compare temperament and character dimensions between violent and non-violent schizophrenic patients and to determine which temperament and character dimensions are predictors of violent behavior in schizophrenia. METHOD: We recruited 102 schizophrenic patients without concomitant substance abuse 4 months prior to the assessment. Diagnoses were based on the SCID-I. Personality dimensions were assessed with the Temperament and Character Inventory and violent behaviors with the Overt Aggression Scale. RESULTS: Higher levels of the temperament dimension novelty seeking and a lower cooperativeness, as a character dimension, were risk factors for violent behavior in schizophrenic patients. DISCUSSION: Our data indicate that schizophrenic patients will show a greater risk for violence according to certain personality configurations and the degree to which environmental events moderate or exacerbate their expression.

Neuromodulation of the inferior thalamic peduncle for major depression and obsessive compulsive disorder.

Neuromodulation of the inferior thalamic peduncle is a new surgical treatment for major depression and obsessive-compulsive disorder. The inferior thalamic peduncle is a bundle of fibers connecting the orbito-frontal cortex with the non-specific thalamic system in a small area behind the fornix and anterior to the polar reticular thalamic nucleus. Electrical stimulation elicits characteristic frontal cortical responses (recruiting responses and direct current (DC)-shift) that confirm correct localization of this anatomical structure. A female with depression for 23 years and a male with obsessive-compulsive disorder for 9 years had stereotactic implantation of electrodes in the inferior thalamic peduncle and were evaluated over a long-term period. Initial OFF stimulation period (1 month) showed no consistent changes in the Hamilton Depression Scale (HAM-D), Yale Brown Obsessive Compulsive Scale (YBOCS), or Global Assessment of Functioning scale (GAF). The ON stimulation period (3-5 V, 130-Hz frequency, 450-msec pulse width in a continuous program) showed significant decrease in depression, obsession, and compulsion symptoms. GAF improved significantly in both cases. The neuropsychological tests battery showed no significant changes except from a reduction in the perseverative response of the obsessive-compulsive patient and better performance in manual praxias of the female depressive patient. Moderate increase in weight (5 kg on average) was observed in both cases.

Obsessive-compulsive disorder in the elderly: A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS).

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD≥65years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample. METHODS: Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

A forced five-dimensional factor analysis and concurrent validity of the Positive and Negative Syndrome Scale in Mexican schizophrenic patients.

UNLABELLED: The heterogeneity of schizophrenic symptomatology is well documented. The positive-negative distinction is limited to cover the entire spectrum of schizophrenic psychopathology in order to describe the various clinical aspects of the disorder. METHOD: We recruited 150 schizophrenic patients between May 2002 and September 2003. Diagnoses were based on a structured clinical interview. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate general psychopathology and symptom severity. For the concurrent validity of the pentagonal model of the PANSS, the BPRS, the CDSS, the OAS and the MMSE were used. RESULTS: The forced five-factor principal-component analysis explained 53.4% of the total variance. There were significant correlations between the clinical rating scales and the five components of the PANSS. DISCUSSION: Our data support a pentagonal model underlying the multidimensional schizophrenic symptomatology as assessed by the PANSS. The five-factor structure of the PANSS in Mexican schizophrenic patients enables further elucidation of the various clinical aspects of schizophrenia.

Genetic markers in biological fluids for aging-related major neurocognitive disorder.

Aging-related major neurocognitive disorder (NCD), formerly named dementia, comprises of the different acquired diseases whose primary deficit is impairment in cognitive functions such as complex attention, executive function, learning and memory, language, perceptual/motor skills, and social cognition, and that are related to specific brain regions and/or networks. According to its etiology, the most common subtypes of major NCDs are due to Alzheimer' s disease (AD), vascular disease (VaD), Lewy body disease (LBD), and frontotemporal lobar degeneration (FTLD). These pathologies are frequently present in mixed forms, i.e., AD plus VaD or AD plus LBD, thus diagnosed as due to multiple etiologies. In this paper, the definitions, criteria, pathologies, subtypes and genetic markers for the most common age-related major NCD subtypes are summarized. The current diagnostic criteria consider cognitive decline leading to major NCD or dementia as a progressive degenerative process with an underlying neuropathology that begins before the manifestation of symptoms. Biomarkers associated with this asymptomatic phase are being developed as accurate risk factor and biomarker assessments are fundamental to provide timely treatment since no treatments to prevent or cure NCD yet exist. Biological fluid assessment represents a safer, cheaper and less invasive method compared to contrast imaging studies to predict NCD appearance. Genetic factors particularly have a key role not only in predicting development of the disease but also the age of onset as well as the presentation of comorbidities that may contribute to the disease pathology and trigger synergistic mechanisms which may, in turn, accelerate the neurodegenerative process and its resultant behavioral and functional disorders.

Additional evidence that genetic variation of MAO-A gene supports a gender subtype in obsessive-compulsive disorder.

Studies have recently reported a sexually dimorphic association between obsessive-compulsive disorder (OCD) and a polymorphism related with variations in MAO-A activity. These observations suggest the possibility of gender differences in genetic susceptibility for OCD. We thus reexamined the MAO-A/EcoRV polymorphism in a sample of 122 OCD patients and 124 healthy subjects. An excess of allele 1 in OCD females with major depression disorder was confirmed as previously reported. This difference was more strongly associated with OCD females than males in the total sample. Finally, we analyzed a sample of 51 OCD trios. Haplotype-based haplotype relative risk (HHRR) analysis of the inheritance of the MAO-A variants revealed in the female probands that 14 out of 19 transmitted the allele 1, providing significant evidence for an allelic association between OCD and MAO-A gene. In conclusion, our findings may provide molecular evidence to identify a clinically meaningful gender subtype. However, an effort should be made to replicate the analysis in larger samples of informative parents using strategies such as transmission disequilibrium test to allow definite conclusions.

Age differences in the sensitivity to clomipramine in an animal model of obsessive-compulsive disorder.

RATIONALE: Subtypes of obsessive-compulsive disorder (OCD) related to age could determine differential response to treatment. OBJECTIVES: To explore possible age differences in the effect of clomipramine in an animal model of OCD. METHODS: The deficits on spontaneous alternation produced by 8-OH-DPAT and the preventing actions of clomipramine, desipramine and WAY 100635 were compared between young and adult rats. RESULTS: No age differences were found in spontaneous alternation. The 5-HT(1A) agonist, 8-OH-DPAT (0.031, 0.125, 0.5 and 2.0 mg/kg, -15 min) produced perseveration in young and adult rats. However, young rats were sensitive to a lower dose of 8-OH-DPAT. Clomipramine (10 mg/kg per three administrations) completely prevented the action of 8-OH-DPAT (0.5 mg/kg) in adult rats. However, this treatment as well as higher doses (15 mg/kg 3 administrations) or injected for longer periods (10 mg/kg 5 administrations) produced weak protective effects (versus 0.125 mg/kg 8-OH-DPAT) or had no action (versus 0.5 mg/kg 8-OH-DPAT) in young animals. WAY 100 635 (0.5 mg/kg) blocked the action of 8-OH-DPAT (0.5 mg/kg) in both young and adult rats. Desipramine (10 mg/kg/3 administrations) lacked of a preventive effect on the 8-OH-DPAT (0.5 mg/kg) action. This result indicated that the 5-HT(1A) receptor is involved in the deficits on spontaneous alternation produced by 8-OH-DPAT. CONCLUSIONS: The present data shows important age differences in the effect of clomipramine in a model of OCD. Such differences could be relevant for the age variations in the response to treatment in clinical practice.

Premorbid adjustment and violent behavior in schizophrenic patients.

UNLABELLED: We examined the influence of premorbid adjustment on violent behavior in schizophrenic patients. There is some evidence that poor premorbid adjustment predicts violent behavior, then we decided to examine this hypothesis further. METHOD: We recruited 72 schizophrenic patients without concomitant substance abuse 6 months prior to the assessment. Diagnoses were based on the SCID-I. Premorbid adjustment was evaluated with the Premorbid Adjustment Scale and violent behaviors with the Overt Aggression Scale. RESULTS: Violent schizophrenic patients showed an overall worse premorbid adjustment during childhood. In addition, the area of "peer relationships" was significantly diminished in several life period sections such as childhood, early and late adolescence in violent patients. DISCUSSION: Our data indicate that difficulties in social relationships during early stages of life may increase the risk of future violent behavior among schizophrenic patients.

Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessive-compulsive disorder with tics.

The polymorphism characterized by a varying number of 48 bp repeats (VNTR) in the dopamine D4 receptor (DRD4) gene was examined in 61 obsessive-compulsive disorder (OCD) probands with and without tics. Most of the OCD patients with tics showed at least one copy of the 7-fold variant compared to those affected subjects without tics (91 vs. 48%, respectively, Yates corrected chi2 = 5.54, P = 0.018). Similarly, a higher number of copies of this common variant were detected in the group of probands displaying tics compared to those OCD's without tics (Yates corrected chi2 = 4.66, P = 0.03). Our study suggests that the seven-repeat allele of the DRD4 gene could be a factor in the phenotypic variance of tics among OCD individuals.

Family study of obsessive-compulsive disorder in a Mexican population.

Twenty seven obsessive-compulsive disorder (OCD) patients were studied at the Instituto Mexicano de Psiquiatría in Mexico City. This is the first sample of OCD patients studied in Latin America. There was a significant sex ratio difference and a significant difference in the type of obsessions and compulsions displayed by males and females. Co-morbidity data demonstrated a high frequency of obsessive-compulsive personality disorders, depression, sexual abuse, suicidal attempts and neurological damage. Approximately one third of OCD cases demonstrated a positive family history. There was a higher than expected frequency of first degree relatives affected with OCD. In addition, this study may support the hypothesis that OCD and tics are genetically related.

Dopamine D4 receptor (DRD4) gene polymorphism in the first psychotic episode.

BACKGROUND: Dopamine D4 receptor (DRD4) has shown some interesting properties at genetic and possibly functional levels. It has been suggested that some molecular variants of the DRD4 gene (e.g., four and seven alleles) could be implicated in the pathogenesis of psychotic disorders. Additionally, the VNTR polymorphism could be implicated in part of the response to treatment with neuroleptics. This study tested the possible association between the 48-bp tandem repeats in exon 3 of the DRD4 gene and patients experiencing their first psychotic episode. METHODS: Patients with a first psychotic episode (FPE, n = 37) were diagnosed and compared with a matched control group (n = 37). The FPE group was subdivided into two categories: those with nonaffective and those with affective psychoses. The variable number of tandem repeats (VNTR) region of the DRD4 gene was amplified by PCR procedures. Chi-square statistics and appropriate corrections and adjustments were used for data analysis. CONCLUSIONS: A significantly lower frequency of the four repeat (4-R) carriers in the FPE group was observed. This association was sustained mainly by the affective psychotic group (chi2 = 9.99 df = 2, p = 0.0073). Although these results require testing with stringent methods, it is suggested that the DRD4-4R allele may confer some protection against psychosis, mainly of the affective subtype.

The dopamine D2 receptor gene TaqI A1 polymorphism and alcoholism in a Mexican population.

The suggested association between the TaqI A1 allele of the dopamine D2 receptor (DRD2) gene with alcoholism was studied comparing the genotypes of 38 controls and 38 ethnic matched alcoholics, drawn from the Mexican population. The alcoholics in our sample suffered from one of the following conditions: delirium tremens, alcohol hallucinosis or uncomplicated alcohol withdrawal. Eighty-eight percent of the controls carried the A1 allele. The frequency of the DRD2 A1 allele in the Mexican sample was higher than reported in Caucasians, but similar to those described in Amerindian groups. There was not any difference in the prevalence or allele frequency between alcoholics and controls. Also, there was no significant differences when alcoholics were subtyped according to severity, age of onset, or positive family history. Alcoholics showed higher scores than controls in the neuroticism and psychoticism subscales on the Eysenck Personality Inventory. However, no relationship between personality traits and genotypes was found. Our results do not support a consistent association between the D2 receptor gene and alcoholism.

Molecular analysis of the phenylalanine hydroxylase gene in Mexican phenylketonuric patients.

The molecular analysis of the human phenylalanine hydroxylase (PAH) gene in Mexican phenylketonuric (PKU) patients is described. We analyzed the restriction fragment length polymorphism (RFLP) haplotypes of five probands and ten non-affected relatives, belonging to four unrelated PKU families. Twenty-nine alleles were typified, corresponding to 12 different haplotypes. Eight RFLP haplotypes corresponded to those described in other populations, while the remaining were unreported haplotypes, appearing both on normal and PKU chromosomes. Using the polymerase chain reaction (PCR) and the allele-specific oligonucleotide assay (ASO), we also screened for the IVS10 mutation, one of the most common PAH gene mutations in Mediterranean countries. Forty-two percent of the PKU chromosomes analyzed bore the IVS10 mutation, although it was present in the heterozygous state in all cases. Our data show an important genetic heterogeneity at the PAH locus in the Mexican population, and report the genetic influence of the Spanish immigration to the American continent.

Lack of association of apolipoprotein E polymorphism in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) could be considered a neurodevelopmental disorder, from several lines of evidence. One of the most widely studied genes in these disorders is the apolipoprotein E gene, particularly allele 4. We analyzed for association among patients with OCD versus normal controls and cognitively impaired patients. There were no significant differences between OCD probands compared with population controls. However, the cognitively impaired group showed a higher frequency of allele apolipoprotein E gene compared with normal controls and patients with OCD.

[Dopaminergic system genes in Mexican schizophrenics]. / Evaluación de genes del sistema dopaminérgico en esquizofrénicos mexicanos.

This investigation reports an association study with alleles of the dopaminergic system genes (tyrosine hydroxylase (TH), D2 and D4 receptors) in schizophrenic patients and non-schizophrenic subjects. The genotypes were typed using a polymerase chain reactions PCR-based CA repeat polymorphisms. There were no significant associations between the studied alleles and schizophrenia. Also, a linkage analysis was performed using the same genes (TH, D2 and D4) in two multiple affected schizophrenic families. There was no linkage among any of three genes and schizophrenia. The maximum lod score (Z = 0.43, theta = 0.10 penetrance 100%) was for the tyrosine hydroxylase gene. Linkage analysis significantly excluded the D2 receptor gene (Z = 5.6, theta = 0.01), assuming an autosomal dominant pattern and complete penetrance, However, when the lod scores were calculated with other penetrance values, they lost significance.