Oussama Kebir

CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta-analysis

The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta‐analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the ‘high risk’ versus ‘low risk’ alleles in cases with dependence versus controls. Studies were analyzed by random‐effects meta‐analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta‐analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of ≥ 16 repeats. Our analysis showed a small effect size (OR = 1.55, P = 0.045), with strong heterogeneity (Q = 19.87, P < 0.01 with I2 = 85%). In line with the polygenic model, our meta‐analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well‐phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms.

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia.

Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case–control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.

Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

Background Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. Principal Findings Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. Conclusions Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelins involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia.

BACKGROUND Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia. METHODS A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions. RESULTS In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia. CONCLUSION This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible.

Confirmation for a delayed inhibition of return by systematic sampling in schizophrenia.

Inhibition of return (IOR) is a phenomenon thought to reflect a mechanism to protect the organism from redirecting attention to previously scanned insignificant locations. A number of studies reported altered IOR in schizophrenia patients with a reduction of its amplitude. However, incomplete sampling of stimulus onset asynchronies (SOAs) makes data on IOR time course incomplete. We examined 14 stabilized young patients with recent onset schizophrenia and 16 healthy controls matched for gender, age, and years of education. Schizophrenia patients (13 males, 1 female) had a mean age of 26.3+/-5.8 years and a mean number of years of study of 9.6+/-3.6. Their illness had a mean duration of 147 weeks. Patients displayed moderate overall slow reaction times (387 ms) in comparison with controls (322 ms). Onset of IOR was found to be delayed in schizophrenia patients appearing between 700 and 800 ms following the cue onset while it appeared at 300 ms in controls. In patients, IOR was constant up to 1100 ms; however, its amplitude was weak with an average of 6 ms. Validity effects (overall and at each SOA value) were uncorrelated to age, years of study, duration of illness, or total or subscale scores on the Positive and Negative Syndrome Scale.

Diethylstilbestrol and risk of psychiatric disorders: A critical review and new insights

Abstract Objectives. We explored whether in utero DES exposure has produced consistent findings with regard to an increased risk of psychiatric disorders. Methods. We reviewed systematically the epidemiological studies investigating a possible association between prenatal DES exposure and risk of psychiatric disorders. Results. We identified 10 relevant studies reporting the psychiatric outcome of offspring with a history of in utero DES exposure compared to a control group. We classified them into four categories: (1) a mail survey in a sample from a randomized double-blind controlled trial of prophylactic DES for first pregnancy in the early 1950s reported that depression and anxiety were twice as frequent in the exposed group compared to the placebo group; (2) five small clinical samples with inconclusive results; (3) two large cohorts of DES-exposed participants: the first study reported a higher lifetime history of weight loss related to anorexia nervosa whereas the second did not found any significant difference; (4) two subsamples from general population cohorts: the first study did not found any significant difference whereas the second reported that exposed women showed a higher rate of incident depression than non-exposed women. Conclusions. The role of prenatal exposure to DES as an environmental risk factor for psychiatric disorders requires more evidence before any conclusions can be drawn. If confirmed, several explanations could be proposed: gene × environment interaction and epigenetic mechanisms, although phenocopy and gene-environment aggregation are plausible.

Association of an UCP4 (SLC25A27) haplotype with ultra-resistant schizophrenia.

AIMS Neuronal uncoupling proteins are involved in the regulation of reactive oxygen species production and intracellular calcium homeostasis, and thus, play a neuroprotective role. In order to explore the potential consequences of neuronal uncoupling proteins variants we examined their association in a sample of Caucasian patients suffering from schizophrenia and phenotyped them according to antipsychotic response. MATERIALS & METHODS Using a case-control design, we compared the frequencies of 15 genetic variants spanning UCP2, UCP4 and UCP5 in 106 French Caucasian patients suffering from schizophrenia and 127 healthy controls. In addition, patients with schizophrenia who responded to antipsychotic treatment were compared with patients with ultra-resistant schizophrenia (URS). This latter population presented no clinical, social and/or occupational remission despite at least two periods of treatment with conventional or atypical antipsychotic drugs and also with clozapine. RESULTS There were no differences in the distribution of the respective alleles between URS and responding patients. However, one haplotype spanning UCP4 was found to be significantly under-represented in URS patients. This relationship remained significant after multiple testing corrections. CONCLUSION Although our sample is of limited size and not representative of schizophrenia as a whole, the association found between the URS group and the UCP4 haplotype is noteworthy as it may influence treatment outcome in schizophrenia.

Methylomic changes during conversion to psychosis

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine–phosphate–guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

Association of Inflammation Genes with Alcohol Dependence/Abuse: A Systematic Review and a Meta-Analysis

The aim of the present work was to systematically review all association studies of inflammation genes with alcohol dependence/alcohol abuse (AD/AA) and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the ‘high-risk’ versus ‘low-risk’ alleles in AD/AA cases versus controls. Data reported in at least three published studies were available for four genetic polymorphisms [TNF-α -238 (rs361525, G/A); TNF-α -308 (rs1800629, G/A); IL-1RA (VNTR [86 bp]n); IL-10 -592 (rs1800896, C/A)]. In total, nine meta-analyses were performed. Of these, only the TNF-α -238 polymorphism showed a significant association with AD/AA (OR = 1.36, 95% CI: 1.05–1.76). This risk remained significant and increased slightly when we considered only patients with advanced alcohol-related liver disease (AALD) (OR = 1.5, 95% CI: 1.13–1.98) but not when we considered only patients without AALD (OR = 1.08, 95% CI: 0.5–2.35). Sensitivity analysis showed that this genetic association is derived from the AALD phenotype rather than from AD. Our approach is limited by our phenotype definition; some studies included chronic heavy drinkers (minimal daily consumption of 80 g for a minimal duration of 10 years) but without a standardized psychiatric assessment.

Verbal but not performance IQ is highly correlated to externalizing behavior in boys with ADHD carrying both DRD4 and DAT1 risk genotypes

OBJECTIVE Attention-deficit/hyperactivity disorder (ADHD) is often associated with reduced IQ and high levels of externalizing behavior (EB). This study tested if DRD4 7-repeat allele and DAT1 10-repeat allele homozygosity interact in modulating correlations between IQ and EB in affected boys. METHODS Boys (n=130) between 6 and 12 years of age diagnosed with ADHD were included in the study. IQ and EB were assessed by WISC-III and Child Behavioral Checklist, respectively. The 40 bp variable number tandem repeat (VNTR) of the DAT1 gene and the 48 bp VNTR of the DRD4 gene polymorphisms were genotyped and 4 subgroups were defined by the presence/absence of the DRD4 7-repeat allele and by the presence/absence of the DAT1 10/10 genotype. Correlation coefficients were compared using the Fishers Z transformation and regression lines by a Potthoff analysis. RESULTS In the total sample, all correlation coefficients between EB score and IQ were non significant. Also, no differences in IQ were observed between the 4 genotype groups. However, different pattern of correlations between IQ and EB score appeared. In boys carrying no or only one genetic risk, IQ and EB score were uncorrelated while in children carrying both risk factors, negative and significant correlations emerged. Notably, correlation of EB to verbal IQ was strong (r=-0.71) and highly significant (P<0.01) in boys carrying both risk alleles. All pair-wise comparisons of correlation coefficients were significant for EB-verbal IQ correlation. Test of coincidence of regression lines did not show significant differences. CONCLUSIONS A specific domain of IQ, namely the verbal quotient is highly correlated to the level of EB in boys with ADHD carrying both dopaminergic risk genotypes. Further investigations are required to replicate these results and determine specificity to ADHD.