Caroline Dubertret

Meta-analysis of DRD3 gene and schizophrenia : Ethnic heterogeneity and significant association in Caucasians

The involvement of dopamine in the etiology of schizophrenia is suggested by a number of neurobiological and pharmacological data, the dopamine D3 receptor (DRD3) being selectively expressed in brain regions which may be specifically involved in the risk for schizophrenia. The gene coding for DRD3 has thus been extensively analyzed. Since the initial report providing substantial evidence for an association of homozygosity of either allele of the gene coding for DRD3 (BalI polymorphisms) with schizophrenia, a flurry of replicating studies has appeared, which have been split into confirmations and nonreplications in North European Caucasian, Mediterranean, Asian, American, and African populations. The involvement of DRD3 polymorphisms thus remains questionable, particularly as no linkage studies have favored a nonrandom segregation of DRD3 alleles and schizophrenia. We performed a metaanalysis from 29 independent samples, from 24 different association studies so far published, allowing the examination of 2,619 schizophrenic patients and 2,517 controls. No significant differences of genotype counts were noted between patients and controls for the whole sample, considering frequency of any genotype. Starting from the high variability of the genotypes in different geographical areas, the impact of ethnic heterogeneity was taken into account. When the studies were reorganized in five groups according to geographical origin of samples, both homozygosity and 1-1 genotype revealed significant heterogeneity (P < 0.05). We specifically found an excess of homozygosity and 1-1 genotype in schizophrenic patients only in the African and Caucasian groups (P < 0.05). The present analysis suggests a small but significant effect of DRD3 in the susceptibility to schizophrenia, at least in Caucasians.

Genetics of dopamine receptors and drug addiction.

Dopamine plays a key role in reward behavior, yet the association of drug dependence as a chronic, relapsing disorder with the genes encoding the various dopaminergic receptor subtypes remains difficult to delineate. In the context of subsequent genome-wide association (GWAS) research and post-GWAS investigations, we summarize the novel data that link genes encoding molecules involved in the dopaminergic system (dopamine receptors, transporter and enzymes in charge of its metabolism) to drug addiction. Recent reports indicate that the heritability of drug addiction should be high enough to allow a significant role for a specific set of genes, and the available genetic studies, which might not be already conclusive because of the heterogeneity of designs, methods and recruited samples, should support the idea of a significant role of at least one gene related to dopaminergic system. Evolutionary changes in primates and non-primate animals of genes coding for molecules involved in dopaminergic system highlight why addictive disorders are mainly limited to humans. Restricting the analyses to more specific intermediate phenotypes (or endophenotypes) such as attention allocation, stress reactivity, novelty seeking, behavioral disinhibition and impulsivity, instead of the broad addictive disorder concept can be instrumental to identify novel genes associated with these traits in the context of genome-wide studies.

Lifetime positive symptoms in patients with schizophrenia and cannabis abuse are partially explained by co-morbid addiction

Recent prospective findings have shown that cannabis use by young people could be a risk factor for psychotic symptoms in adulthood, but the long-term impact of cannabis abuse on the clinical features of declared schizophrenia remains to be explored. We assessed the independent influence of cannabis abuse on the clinical symptoms of schizophrenia, after controlling for frequently co-occurring addictive disorders. Patients with schizophrenia, and with (N=66), or without (N=139) cannabis abuse, were compared for lifetime positive and negative symptoms, taking into account presence of any other addictive disorders. The incidence of the abuse of drugs other than cannabis was nearly five times greater amongst patients with both schizophrenia and cannabis abuse. When the analyses were limited to subjects with no other abuse, less avolution and fewer apathy symptoms were still detected in patients with schizophrenia and cannabis abuse than in those with no abuse (p=0.0001). In contrast, between-group differences for positive symptoms were abolished when multiple substance abuses were taken into account. The strong association between cannabis abuse and fewer negative symptoms in schizophrenia was thus replicated in this sample, but once co-morbid addictive disorders had been controlled no influence of cannabis abuse on hallucinations was detected. Distinguishing the effects of co-occurring addictive disorder(s) in patients with schizophrenia and cannabis dependence may thus be important when attempting to analyse the impact of cannabis abuse.

Impulsiveness as the intermediate link between the dopamine receptor D2 gene and alcohol dependence.

Objectives Reinforcement and reward processes have been proposed as being an intermediate link between the risk for alcohol dependence and the gene coding for the dopamine receptor D2 (DRD2). This hypothesis remains open to speculation, and personality traits such as impulsiveness, a core dimension in addictive disorders, should also be taken into account. For instance, recent evidence in rats showed that DRD2 antagonists might increase impulsivity in decreasing the value of delayed rewards. Methods Considering the pro‐impulsiveness role of ethanol observed in clinical practice and epidemiological studies, we analysed the Barratt impulsiveness scores in a sample of 92 alcohol‐dependent French patients (57 men and 35 women), according to the TaqI A polymorphism of the DRD2 gene. Results A2/A2 and A1/A2 genotypes were significantly associated with a higher global impulsiveness than A1/A1 genotype (P = 0.02 and P =0.03, respectively). Conclusions We propose that reward‐related impulsiveness may constitute a risk factor for alcohol dependence, and that this core temperament could be partly mediated by the DRD2 gene.

Predictors of postpartum depression: Prospective study of 264 women followed during pregnancy and postpartum

The prevalence of postpartum depression is approximately 13%. Postpartum depression is associated with a higher maternal morbidity and mortality, and also with pervasive effects on the emotional, cognitive and behavioral development of the child. The aim of our study was to identify socio-demographic, psychosocial and obstetrical risk factors of postpartum depression in a middle class community sample, using a prospective design. We enrolled consecutively 312 pregnant outpatients in a single maternity unit. The first assessment was conducted between 32 and 41 weeks gestation, and a second time between 6 and 8 weeks after delivery. Depressive symptoms were measured using the French version of the Edinburgh Postnatal Depression Scale (EPDS). A cut-off score of 12/30 or above was considered as indicative of Major Depression. Of the initial sample of 312 women, 264 (84.6%) were followed-up between 6 and 8 weeks after delivery and considered for analysis. Depression during pregnancy, migrant status, and physical abuse by the partner were independently associated with postpartum depression when considered together, whereas physical complications were significantly associated with postpartum depression only when adjusting for antenatal depression. Depression during pregnancy, history of physical abuse, migrant status and postpartum physical complications are four major risk factors for postpartum depression.

The executive control of attention differentiates patients with schizophrenia, their first-degree relatives and healthy controls

Attentional and executive impairments have been reported in patients with schizophrenia and in their healthy first-degree relatives. However, its nature remains unclear and discrepancies between studies have been observed. These might be due to differences in the clinical severity of the illness or in sociodemographic factors. The objective of the present work was to explore the efficiency of three attention networks: alerting, orienting and executive control (conflict inhibition) defined anatomically, using patients, their relatives and controls, assessing the possibility to use them as endophenotypes. We used three tests, the Attention Network Test (ANT), the Wisconsin Card Sorting Test (WCST) and the Stroop Test, and compared 52 patients with schizophrenia, 55 of their first-degree relatives and 53 unrelated healthy controls, taking into account demographic variables (age, sex and years of education) and clinical symptoms of schizophrenia. Patients had a longer overall mean reaction-time (p<0.001), and took longer to resolve the ANT conflict (ANTc) (p=0.04) than the control group. In the schizophrenia group, the SSPI disorganization score was significantly correlated to the ANTc performance. Additionally, first-degree relatives of patients with schizophrenia also performed significantly worse than controls in attention performance test. Our findings support a specific deficit in executive control of attention in patients with schizophrenia. This deficit was shown to be correlated with the intensity of the disorganization score in patients. Relative presented an intermediate phenotype between patients and controls; the ANT reaction time (but not the ANTc) may thus be considered as possible endophenotype marker for schizophrenia.

Association and excess of transmission of a DRD2 haplotype in a sample of French schizophrenic patients.

The gene which codes for dopamine receptor D2 (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene gave conflicting results, potentially because of the differences in methodology (linkage versus association studies), and the different loci analyzed (the DRD2 gene having many polymorphisms). We used a progressive strategy with three different approaches (case/control, haplotype relative risk and transmission disequilibrium test) and investigated two genetic polymorphisms (TaqI B1/B2 and TaqI A1/A2, spanning the coding region of the DRD2 gene) in 50 patients with DSM-IV diagnoses of schizophrenia, in their 100 parents and in 50 healthy, matched controls. Firstly, we found a significant excess of the two alleles (B2 and A2) in the schizophrenic group compared to unaffected controls. Secondly, we found an excess of transmission from the parents to their affected children, using the haplotype relative risk design applied to the B2A2 haplotype. Finally, the transmission disequilibrium test showed evidence for linkage between B2A2 haplotype and schizophrenia. The significant excess of the B2A2 haplotype in schizophrenic patients is specifically observed in a subsample of patients with a disease onset occurring after 20 years of age. As the haplotype contains nearly the entire DRD2 gene, we found convergent evidence in our sample for a significant role of the DRD2 gene in the risk for schizophrenia. This haplotype may be more specifically involved in the disorders onset at a later age in some patients, or, alternatively, may be implicated as a modifying factor acting on age of onset.

Generalizability of clinical trial results for bipolar disorder to community samples: findings from the national epidemiologic survey on alcohol and related conditions

BACKGROUND Research on the generalizability of clinical trial results for bipolar disorder is limited. The present post hoc study sought to quantify the generalizability of clinical trial results in individuals with DSM-IV bipolar disorder to a large representative community sample. METHOD Data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large, nationally representative sample of 43,093 adults from the United States population. We applied a standard set of eligibility criteria representative of clinical trials to all adults with DSM-IV bipolar depression (n = 785) or mania (n = 724) in the past 12 months and then to a subsample of participants seeking treatment for bipolar depression (n = 276). Our aim was to determine the proportion of participants with bipolar depression or acute mania who would have been excluded from a clinical trial by typical eligibility criteria. RESULTS We found that more than 5 of 10 participants with bipolar depression (58.17%) or mania (55.75%) would have been excluded by at least 1 eligibility criterion. In the subgroup of participants with bipolar depression who sought treatment, the exclusion rate by at least 1 criterion was higher (63.87%). Having a significant risk of suicide was the criterion excluding the highest percentage of participants in the bipolar depression samples, while having a current DSM-IV diagnosis of alcohol abuse or dependence was the one leading to the greatest exclusion rate in clinical trials for participants with acute mania. Exclusion rates were higher for participants with bipolar I depression compared with those with bipolar II depression. CONCLUSIONS Traditional clinical trials tend to exclude a majority of individuals with bipolar disorder. Clinical trials should carefully consider the impact of eligibility criteria on the generalizability of their results and explain the rationale for their use. Future trials should weigh the trade-offs between internal validity and the representativeness of the study.

Child Marriage in the United States and Its Association With Mental Health in Women

OBJECTIVE: Despite the devastating impact of child marriage (marriage before the age of 18 years) on health, no study has yet evaluated its impact on mental health in the general adult population. This article presents nationally representative data on the prevalence, sociodemographic correlates, and psychiatric comorbidity of child marriage among women in the United States. METHODS: Data were drawn from the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions. We limited our analyses to the sample of women (N = 24 575) with a known age at first marriage, of whom 18 645 had been or were presently married. RESULTS: The prevalence of child marriage among women was 8.9%. Demographic factors associated with child marriage were black and American Indian/Alaska Native ethnicities, age at interview of >45 years, low educational level, low income, and living in the South and rural areas of the United States. The overall lifetime and 12-month rates of psychiatric disorders were higher for women who married as children, compared with women who married as adults. In addition, women who married as children were more likely to seek and access health services, compared with women who married in adulthood. CONCLUSIONS: Child marriage increases the risk of lifetime and current psychiatric disorders in the United States. Support for psychiatric vulnerabilities among women married in childhood is required.

A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes

BACKGROUND The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1. METHODS We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case-control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1. RESULTS Case-control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p=0.01, Odds Ratio=1.5, 95% Confidence Interval=1.1-2.2), and the intergenic rs2242592 (p=2.10(-4), OR=1.8, 95%CI=1.3-2.5). A significant SNP-SNP interaction was also found (p<10(-5), OR=2.0, 95%CI=1.6-2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage. CONCLUSIONS Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.