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Biomedical subjects

P Gorwood

Publications and source records attributed to P Gorwood.

At least 19 recordsLinked to original sources
PubMed2006

Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.

Adult↗
PubMed2005

Meta-analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder.

INTRODUCTION: Molecular genetic research has mainly focused on the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) genes in attention-deficit hyperactivity disorder (ADHD). A recent meta-analysis showed that the DRD4 gene has a significant role in the vulnerability to ADHD. OBJECTIVES: With an equal number of positive and negative association studies between the 10-repeat of the DAT gene and ADHD, a meta-analysis is required for this other candidate gene. METHODS: We re-analysed the 13 published family-based association studies between ADHD and the DAT gene. Following recent recommendations, different biases were specifically assessed, such as the sample-size effect and the time effect. RESULTS: The meta-analysis showed no significant association between ADHD and the DAT gene (P = 0.21), but an important between-samples heterogeneity (P = 0.0009). Odds ratios above 1 are mostly observed in studies with a small number of informative transmissions, and decrease with larger sample size. CONCLUSIONS: Contrary to what was found for the DRD4 gene, the 10-repeat allele of the DAT gene has at most a minor role in the genetic susceptibility of ADHD. The different biases detected herein probably explain the initial impression of a significant impact of the DAT gene on hyperactivity.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia.

The expression of serotonin type 6 receptor (5-HT(6)) in limbic and cortical regions of the brain, and its high affinity for atypical antipsychotics suggest that its encoding gene may play a role in the pathogenesis of schizophrenia. We firstly performed a meta-analysis of the C267T polymorphism of the 5-HT(6) gene in schizophrenia, based on four different case/control studies, and showed that the allelic distribution is not significantly different between patients and controls, even when taking into account the role of between samples heterogeneity. We then recruited 103 trios (patients with Diagnostic and Statistical Manual Mental Disorders, 4th ed. (DSM-IV) diagnosis of schizophrenia and their parents), and investigated the C267T polymorphism of the 5-HT(6) receptor gene with regard to family-based association study approach (haplotype relative risk (HRR) and transmission disequilibrium test (TDT)). We found no excess of transmission of one allele from the parents to their affected children, using the HRR (P = 0.60), as well as no evidence for linkage between C267T polymorphism and schizophrenia, using the TDT (P = 0.71). Furthermore, the 267T allele frequency was comparable in the different subgroups defined on age at onset, family history of schizophrenia, treatment response, and subtypes of patients based on positive versus negative predominant symptoms. These data do not support the idea that the 5-HT(6) receptor gene plays a major role in the etiopathogenesis of schizophrenia.

Alleles↗
PubMed2004

Rheumatoid arthritis and schizophrenia: a negative association at a dimensional level.

There is wide evidence for a decreased risk of rheumatoid arthritis in patients with schizophrenia. Nevertheless, very few studies have looked at the risk of schizophrenia in a group of patients with rheumatoid arthritis. We prospectively investigated, with the SCL-90R, 220 consecutive outpatients with rheumatoid arthritis and 196 consecutive outpatients with various medical conditions, half of them suffering from psoriatic arthritis (a medical condition close to rheumatoid arthritis). The SCL-90R appears to be a valuable tool to distinguish patients with schizophrenia from the outpatients of our sample, the former having more "paranoid ideation" (p = 0.004) and more "psychoticism" (p < 0.001) than the latter. The "paranoid ideation" dimension was significantly lower (25% decrease) in the sample of patients with rheumatoid arthritis compared to the combined control group (p = 0.005), ratings under the median value being more frequent in the former group (p = 0.025). Confounding factors might not explain this difference according to the regression logistic analysis performed. As patients with rheumatoid arthritis have a lower score of paranoid ideation than controls in our sample, even after controlling for age, gender and severity of the disease, these data represent further evidence for a decreased risk of schizophrenia in individuals with rheumatoid arthritis.

Adult↗
PubMed2004

Generalized anxiety disorder and major depressive disorder comorbidity: an example of genetic pleiotropy?

Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are the most common type of anxiety-mood comorbidity. Up to 80% of subjects with lifetime GAD also have a comorbid mood disorder during their lifetime. Many hypotheses have been raised to explain such high comorbidity. Pleiotropy, i.e. a single genetic mutation explains (apparently) different disorders, is one of them and is hereby reviewed. Importance and reliability of GAD and MDD comorbidity (1); Evidence in favour of co-aggregation of GAD and MDD within families (the risk of one disorder in a proband increasing the risk for the other in relatives) (2); substantial heredity for both disorders according to twin studies with evidence for genetic correlation of unity between the two disorders (3); existence of numerous mechanisms (4) potentially linking the two disorders to common vulnerability genes, are all in accordance with such a hypothesis. Some examples of potentially shared mechanisms (such as CRF dysregulation or abnormal transcription factors) and possible common vulnerability genes (for example, the serotonin transporter gene) are given to highlight the pleiotropy hypothesis.

Anxiety Disorders↗
PubMed2003

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.

Alcoholism↗
PubMed2002

5-HT(2A) gene promoter polymorphism as a modifying rather than a vulnerability factor in anorexia nervosa.

The A allele of the 5-HT(2A) gene (-1438A/G polymorphism) has been associated with anorexia nervosa in four studies, but not in three others. One possibility to explain such a discrepancy is that the A allele acts as a modifying rather than a vulnerability allele. To test this hypothesis, we increased our initial sample of 102 trios left open bracket Mol. Psychiatry 7 (2002) 90 right open bracket with 43 new patients with anorexia nervosa and 98 healthy controls. In addition to confirming the absence of association on the global sample of 145 patients, we found that patients with the A allele had a significantly later age at onset of the disease (P = 0.032). Furthermore, the A allele was also transmitted with an older age at onset (P = 0.023) using a quantitative-trait TDT approach. The A allele may thus act as a modifying factor (delaying onset), potentially explaining variations of allele frequency across samples, in which differences in average age at onset are not only possible, but also expected. Taking into account vulnerability genes, but also genes modifying the expression of the disorder, will help to disentangle the complexity of the etiological factors involved in anorexia nervosa.

Adult↗
PubMed2002

The 5-HT(2A) -1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres.

Several case-control association studies have raised the possibility that the A allele of a -1438 G/A polymorphism in the type 2A serotonin receptor (HTR2A) gene may be a risk factor for anorexia nervosa. However the absence of linkage and the existence of negative association studies raise the possibility of false positive findings, resulting from population stratification or lack of statistical power. To address this controversy we recruited a sample of 316 patients with anorexia nervosa from six European centres, and utilised a family-based transmission disequilibrium (TDT) approach to analyse the HTR2A-1438 G/A polymorphism. Age at onset and minimal BMI were also taken into consideration in order to detect clinical heterogeneity or a quantitative trait effect. The TDT approach showed that the A allele was transmitted 133 times and not transmitted 148 times (McNemar chi(2) = 0.29, df = 1, P = 0.59). Also, the haplotype-based haplotype relative risk method showed no evidence for association of the A allele, in samples from each centre (chi(2) < 2.15, df = 1, P > 0.14) and in the total sample (chi(2) = 0.55, df = 1; P = 0.46). Furthermore, we found no evidence for heterogeneity of the A allele frequency between samples (chi(2) = 2.54, df = 4, P = 0.64), either according to minimal-BMI (F1/242 = 2.14, P = 0.45) or age at onset (F1/224 = 2.39; P = 0.12). QTL-TDT analyses also showed no direct role of the A allele on these traits. We thus found no evidence for a significant role of the 5-HT(2A) gene in anorexia nervosa. Previous results may have been exposed to stratification bias (which we controlled by the TDT method) and/or the risk of type 1 error (from which we were less exposed because of the sample size).

Adolescent↗
PubMed2001

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 disorder's onset at a later age in some patients, or, alternatively, may be implicated as a modifying factor acting on age of onset.

Adult↗
PubMed2001

The genetics of addiction: alcohol-dependence and D3 dopamine receptor gene.

Alcohol-dependence is a complex phenotype, with behavioral, psychological, pharmacological, medical and social dimensions. Aggregation studies, adoption and twin researches have demonstrated that the vulnerability to alcohol-dependence is at least in part linked to genetic factors, the genetic vulnerability to alcoholism being mainly not substance-specific. There are numerous candidate genes, but the D3 dopamine receptor is specifically located in the limbic area, and in particular in the nucleus accumbens, which are involved in reward and reinforcement behavior. Furthermore, a previous collaborative study showed that homozygosity for the Ball DRD3 locus was more frequently observed in opiate dependent patients with high sensation seeking scores. In this study, we analyzed the distribution of Ball DRD3 polymorphism in a new sample of 131 French male alcoholic-patients (DSM III-R criteria) and 68 healthy controls matched for sex and origins. Although we replicated the higher sensation seeking score in alcohol-dependent patients with comorbid dependence, we found no significant difference in the DRD3 gene polymorphism between controls and alcoholic patients, regardless of sensation seeking score, addictive or psychiatric comorbidity, alcoholism typology, and clinical specificities of alcoholism. There is good evidence that gene coding for the dopamine receptor D3 does not play a major role in the genetic vulnerability to alcoholism.

Adult↗
PubMed2001

Clinical characteristics of familial versus sporadic alcoholism in a sample of male and female patients.

Presence of a family history of alcoholism may predict clinical characteristics in affected subjects, such as an earlier age at onset. More frequent and severe social maladjustment and somatic complications are also regularly cited for familial alcoholism, although subject to many other confusing factors. We analysed the clinical specificities of 79 alcohol-dependent inpatients according to the absence versus presence of family history of alcoholism. Patients were evaluated for lifetime psychiatric morbidity with the Diagnostic Interview for Genetic Studies (DIGS), for somatic complications with a systematic screening list, and first-degree relatives (N = 428) were assessed with the Family Inventory Schedule and Criteria (FISC). Age at onset and social complications were predicting familial versus sporadic alcoholism, even when considering censored data and/or interaction between variables. But differences became non-significant when excluding patients with antisocial personality. If age at onset effectively appears to be the most informative characteristic for predicting familial versus sporadic alcoholism, it seems that it may be necessary in future studies to systematically take into account antisocial personality diagnosis, because of a probable contamination.

Adult↗
PubMed2001

Biological markers for suicidal behavior in alcohol dependence.

Alcohol-dependent populations have a high lifetime suicide rate (between 7 and 15%, relative risk = 7), and alcoholism is one of the two psychiatric disorders most frequently found in suicidal cases (between 15 and 25%). Biological factors that would detect patients at risk could thus be of value. Carbohydrate-deficient transferrin, monoamine oxidase B, soluble interleukin-2 receptor and cholesterol have been proposed as markers of suicidal risk in alcohol-dependent patients, although nonspecific and with low predictive value. On the other hand, there is large and convergent data stressing the importance of serotonin dysregulation as increasing the risk for aggressive behaviour toward the self, although it is not clear whether serotonin is involved through the altered behavior inhibition system, enhancement of anxiety and depression, or association with specific subtypes of alcohol-dependence, such as early-onset type II alcoholism. Considering the complex but significant impact of alcohol on serotonin metabolism and turnover, it is likely that serotonin mediates a large part of the proneness of ethanol to commit impulsive-aggressive behavior.

Alcoholism↗
PubMed2000

Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior.

BACKGROUND: Dysfunction of serotoninergic transmission could predispose to excessive alcohol consumption and dependence. The functional polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with different disorders, including alcoholism. Considering the likelihood of heterogeneity in the "alcohol dependence" phenotype, 5-HTTLPR may be more specifically implicated in subsamples of patients or in related traits of alcoholism, such as impulsivity. METHODS: We analyzed the role of this functional polymorphism in the risk for suicide attempt in a population of male alcohol-dependent subjects. One hundred ten male alcohol-dependent patients (DSM-III-R criteria), French for at least two generations, were personally interviewed with the Diagnostic Interview for Genetic Studies and compared with 61 unaffected blood donors. RESULTS: The "short" (S) allele of the 5-HTTLPR appeared to be unrelated to alcohol dependence and comorbid depression in our sample, but was found associated with an increased risk for suicide attempts. This association was predominantly observed in severe and repetitive suicide attempts, with a significant dose effect of the S allele (0, 1, or 2) on the number and the severity of suicide attempts. CONCLUSIONS: Mood disorders and alcohol dependence may interact with a genetic (relative) deficiency in serotonin reuptake, thereby increasing the risk for aggressive/impulsive behaviors such as suicide attempts.

Adult↗
PubMed2000

Relationships between antisocial personality and alcoholism: genetic hypotheses.

Genetic factors explain a non-negligible part of the vulnerability to alcohol dependence, the genetic influence in males being estimated at around 60%. The search for gene(s) potentially implicated in alcoholism is counteracted by the clinical heterogeneity of alcoholism, but also by heterogeneity of the etiologic factors involved. It is thus necessary to redefine more specific phenotypes with more simple determinism, and to focus on more specific subsets of candidate genes. In this view, the existence of co-occurrence (presence at the same time, whatever the cause) between antisocial personality and alcoholism is frequently reported. Three hypotheses have been previously proposed to explain this co-occurrence. Firstly, it could be a pure artefact or contamination, due to common items in diagnostic manuals widely used, such as the DSM or ICD. Secondly, antisocial personality and alcoholism could share common etiologic factor(s), and determine a 'real' co-morbidity. Finally, common genetic factors between these two disorders may exist, with the observation of a co-transmission of both disorders more often than expected by chance alone, meaning the existence of co-aggregation. Each of these three hypotheses will be reviewed and discussed.

Alcoholism↗