Lucia Romo

Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: Association with subtype, body-mass index, severity and age of onset.

Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptins effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

First positive reactions to cannabis constitute a priority risk factor for cannabis dependence

AIM To assess the association between first reactions to cannabis and the risk of cannabis dependence. DESIGN A cross-sectional population-based assessment in 2007. SETTING A campus in a French region (Champagne-Ardennes). PARTICIPANTS A total of 1472 participants aged 18-21 years who reported at least one life-time cannabis consumption, of 3056 students who were screened initially [the Susceptibility Addiction Gene Environment (SAGE) study]. MEASUREMENTS Positive and negative effects of first cannabis consumptions, present cannabis dependence and related risk factors were assessed through questionnaires. FINDINGS   The effects of first cannabis consumptions were associated dose-dependently with cannabis dependence at age 18-21 years, both according to the transversal approach of the SAGE study and to the prospective cohort of the Christchurch Health and Development Study (CHDS) assessed at the age of 25 years. Participants of the SAGE study who reported five positive effects of their first cannabis consumption had odds of life-time cannabis dependence that were 28.7 (95% confidence interval: 14.6-56.5) higher than those who reported no positive effects. This association remains significant after controlling for potentially confounding factors, including individual and familial variables. CONCLUSIONS This study suggests an association between positive reactions to first cannabis uses and risk of life-time cannabis dependence, this variable having a central role among, and through, other risk factors.

Estrogen Receptor 1 Gene (ESR1) is Associated with Restrictive Anorexia Nervosa

Anorexia nervosa (AN) is a highly heritable young-onset psychiatric illness the etiology of which remains unknown. Estrogen alpha and beta receptors, encoded by ESR1 and ESR2 genes, are involved in food intake regulation and eating behavior, and may have a potential role in AN. We performed a family-based association study of 17 single-nucleotide polymorphisms (SNPs) encompassing ESR1 and ESR2 genes in a cohort of 321 French AN families. We attempted to replicate this finding in a cohort of 41 restrictive AN (RAN) families and in a population-based study of 693 young women. Using the transmission disequilibrium test, a significant over-transmission was detected between AN and ESR1 rs726281 and rs2295193. These SNPs and another among ESR1 were more specifically associated with the RAN subtype (rs726281, p=0.005, odds ratio (OR)=2.1, 95% confidence interval (95% CI)=1.2–3.6; rs3798577, p=0.021, OR=1.6, 95% CI=1.1–2.3; and rs2295193, p=0.007, OR=1.7, 95% CI=1.2–2.5). A large eight-SNPs haplotype of ESR1 gene was also associated with AN (p<0.0001, OR=3.1, 95% CI=1.8–5.1). Association of ESR1 SNPs and RAN was driven by paternal over-transmissions (p<0.0001, OR=3.7, 95% CI=1.9–7.3). Furthermore, we confirmed the preferential paternal over-transmission of the ESR1 rs726281 on the independent German sample of 41 RAN trios (p=0.025, OR=3, 95% CI=1.1–8.3). Finally, rs3798577 was associated with eating disorders in a population-based sample of 693 women (p<0.01). Our findings are strongly in favor of an association between ESR1 polymorphisms and AN. In particular, ESR1 gene confers a high risk of vulnerability to the restrictive subtype of AN, and suggests that the estrogen pathway has to be further analyzed in AN.

La dysrégulation émotionnelle est-elle une des composantes du trouble déficit d’attention/hyperactivité ?

INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children and adolescents. It is characterized by age-inappropriate inattention/impulsiveness and/or hyperactivity symptoms. ADHD shows a high comorbidity with oppositional defiant disorder (ODD), a disorder that features symptoms of emotional lability. Due to this comorbidity, emotional lability was long considered a secondary consequence of ADHD, which could arise under the influence of environmental factors such as inefficient parenting practices, as part of an ODD diagnosis. In this model of heterotypic continuity, emotional lability was considered not to play any causal role regarding ADHD symptomatology. LITERATURE FINDINGS As opposed to this view, it is now well established that a large number of children with ADHD and without any comorbid disorder exhibit symptoms of emotional lability. Furthermore, recent studies have found that negative emotionality accounts for significant unique variance in ADHD symptom severity, along with motor-perceptual and executive function deficits. Barkley proposed that ADHD is characterized by deficits of executive functions, and that a deficiency in the executive control of emotions is a necessary component of ADHD. According to this theory, the extent to which an individual with ADHD displays a deficiency in behavioral inhibition is the extent to which he or she will automatically display an equivalent degree of deficiency in emotional inhibition. However, not all children with ADHD exhibit symptoms of emotional lability, and studies have found that the association between emotional lability and ADHD was not mediated by executive function or motivational deficits. Task-based and resting state neuroimaging studies have disclosed an altered effective connectivity between regions dedicated to emotional regulation in children with ADHD when compared to typically developing children, notably between the amygdala, the prefrontal cortex, the hippocampus and the ventral striatum. Morphological alterations of the amygdala have also been reported in previous structural studies in children with ADHD. DISCUSSION Emotional lability can result from different neurobiological mechanisms. In particular, bottom-up and top-down processes can be opposed. Bottom-up related emotional dysregulation involves an increased emotional reactivity, and is thought to be linked to the automatic evaluative activity of the amygdala. Top-down mechanisms are associated with the regulation of such activity, and rely on a prefrontal network including the lateral prefrontal cortex, the anterior cingulate cortex and the orbitofrontal cortex. Since various neuropsychological impairments and alterations in multiple brain networks have been implicated in the etiology of ADHD, contemporary models emphasize its neuropsychological heterogeneity. It is therefore likely that some but not all children with ADHD will exhibit neurobiological alterations in circuits dedicated to emotional regulation, possibly at different levels. Future research will have to identify the different causal pathways and to decide whether emotional lability represents a criterion to subtype ADHD diagnoses. CONCLUSION Emotional dysregulation is now known to play a causal role regarding ADHD symptomatology. Along with executive functioning, reaction time variability and potentially delay aversion, emotional dysregulation should therefore be included in future theoretical models of ADHD, as well as in clinical practice when identifying the major impairments in this diagnostic group and when deciding therapeutic strategies.

Self-reported dependence on mobile phones in young adults: a European cross-cultural empirical survey

Background and aims Despite many positive benefits, mobile phone use can be associated with harmful and detrimental behaviors. The aim of this study was twofold: to examine (a) cross-cultural patterns of perceived dependence on mobile phones in ten European countries, first, grouped in four different regions (North: Finland and UK; South: Spain and Italy; East: Hungary and Poland; West: France, Belgium, Germany, and Switzerland), and second by country, and (b) how socio-demographics, geographic differences, mobile phone usage patterns, and associated activities predicted this perceived dependence. Methods A sample of 2,775 young adults (aged 18–29 years) were recruited in different European Universities who participated in an online survey. Measures included socio-demographic variables, patterns of mobile phone use, and the dependence subscale of a short version of the Problematic Mobile Phone Use Questionnaire (PMPUQ; Billieux, Van der Linden, & Rochat, 2008). Results The young adults from the Northern and Southern regions reported the heaviest use of mobile phones, whereas perceived dependence was less prevalent in the Eastern region. However, the proportion of highly dependent mobile phone users was more elevated in Belgium, UK, and France. Regression analysis identified several risk factors for increased scores on the PMPUQ dependence subscale, namely using mobile phones daily, being female, engaging in social networking, playing video games, shopping and viewing TV shows through the Internet, chatting and messaging, and using mobile phones for downloading-related activities. Discussion and conclusions Self-reported dependence on mobile phone use is influenced by frequency and specific application usage.

Towards a Validation of the Three Pathways Model of Pathological Gambling

With the aim of validating the three pathways hypothesis of pathological gambling (Blaszczynski and Nower in Addiction 97:487–499, 2002) 372 pathological gamblers meeting DSM IV (2000) criteria were assessed via a structured clinical interview as well as being subjected to personality tests and evaluation of their gambling practices. Our results show that it is possible to identify three subgroups corresponding to the three pathways: behaviourally conditioned problem gamblers, emotionally vulnerable problem gamblers and antisocial impulsivist problem gamblers. Our results particularly demonstrate that impulsivist gamblers preferentially choose semi-skilful gambling (horse racing and sports gambling) whereas emotionally vulnerable gamblers are significantly more attracted to games of chance (one-armed bandits, scratch cards, etc.) This led us to propose a functional presentation of the three pathways model which differs somewhat from the Blaszczynski and Nower presentation.

Role of the neurotrophin network in eating disorders' subphenotypes: Body mass index and age at onset of the disease

Eating disorders (ED) are severe psychiatric diseases that most likely result from, and are sustained by socio-cultural, psychological and biological factors. We explored whether members of the neurotrophin family are disease-modifying factors of quantitative traits, potentially contributing to the outcome or prognosis of the disease. We studied lifetime minimum and maximum body mass index (minBMI and maxBMI) and age at onset of the disease in a sample of 991 ED patients from France, Germany, Italy and Spain and analysed 183 genetic variants located in 10 candidate genes encoding different neurotrophins and their receptors. We used a hierarchical model approach to include prior genetic knowledge of the specific and found that variants in CNTF, in its receptor CNTFR, and in NTRK2 were significantly associated with a lower age at onset of the ED. In addition, one variant in NTRK1 was associated with a higher minBMI. The results suggest that for these two subphenotypes, CNTF, CNTFR, NTRK1 and NTRK2 might act as disease-modifying factors and add preliminary evidence to the global hypothesis that EDs are the result of complex interactions and reciprocal controls between the immune, endocrine and central nervous systems.

Prevalence and characteristics of addictive behaviors in a community sample: A latent class analysis

While addictions to substances such as alcohol, tobacco, and other drugs have been extensively investigated, interest has been growing in potential non-substance-related addictive behaviors (e.g., excessive gambling, buying or playing video games). In the current study, we sought to determine the prevalence and characteristics of a wide range of addictive behaviors in a general population sample and to identify reliable subgroups of individuals displaying addictive behaviors. Seven hundred seventy participants completed an online survey. The survey screened for the presence and characteristics of the main recognized substance and behavioral addictions (alcohol, tobacco, cannabis, other drugs, gambling, compulsive shopping, intensive exercise, Internet and mobile phone overuse, intensive work involvement, and overeating) in a three-month period. Key aspects of addiction were measured for each reported behavior, including negative outcomes, emotional triggers (positive and negative emotional contexts), search for stimulation or pleasure, loss of control, and cognitive salience. Latent class analysis allowed us to identify three theoretically and clinically relevant subgroups of individuals. The first class groups problematic users, i.e., addiction-prone individuals. The second class groups at-risk users who frequently engage in potentially addictive behaviors to regulate emotional states (especially overinvolvement in common behaviors such as eating, working, or buying). The third class groups individuals who are not prone to addictive behaviors. The existence of different groups in the population sheds new light on the distinction between problematic and non-problematic addiction-like behaviors.

L'image de soi de l'alcoolodépendant à travers l'échelle Tennessee du concept de soi: Etude comparative entre hommes et femmes

Resume L’hypothese d’une image de soi negative chez les alcooliques a ete validee par des etudes des annees 1970. A travers les changements de la societe, les representations de la maladie se sont modifiees. On peut se demander si le fait que l’alcoolisme soit aujourd’hui davantage percu comme une maladie peut avoir influence l’image de soi des alcooliques. L’echelle Tennessee du Concept de soi et l’Inventaire d’estime de soi ont ete administres a 30 patients alcooliques et a 30 participants controles. Les resultats montrent que les alcooliques ont une image d’eux-memes plus negative que le groupe controle. Les femmes alcooliques ont une estime de soi plus faible que les hommes alcooliques. L’evolution de la representation de la maladie alcoolique semble avoir contribue a ameliorer l’image de soi des alcooliques. Les changements de la condition feminine ont permis aux femmes alcooliques une amelioration de leur image de soi, qui tend a se rapprocher de celle des hommes alcooliques.