Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%.

Cognitive appraisal and life stress moderate the effects of the 5-HTTLPR polymorphism on amygdala reactivity.

The short allele of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is associated with increased amygdala activation in response to emotional stimuli. Although top-down processes may moderate this association, available evidence is conflicting, showing the genotype influence on amygdala reactivity to be either decreased or increased during emotion regulation. Because the effects of the 5-HTTLPR polymorphism on amygdala reactivity are also conditional on self-reported life stress, differences in life stress exposure may account for this apparent discrepancy.

5-HT1A gene promoter polymorphism and [18F]MPPF binding potential in healthy subjects: a PET study.

Background: Previous Positron Emission Tomography (PET) studies of 5-HT1A receptors have shown an influence of several genetic factors, including the triallelic serotonin transporter gene-linked polymorphic region on the binding potential (BPND) of these receptors. The aim of our study was to investigate the relationship between a 5-HT1A promoter polymorphism and the binding potential of another selective 5-HT1A receptor antagonist, [18F]MPPF, in healthy subjects.

Methods: Thirty-five volunteers, including 23 women, underwent an [18F]MPPF scan and were genotyped for both the C(-1019)G 5-HT1A promoter polymorphism and the triallelic serotonin transporter gene-linked polymorphic region.

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.

Genetics and personality affect visual perspective in autobiographical memory.

Major depression is associated with a decrease of 1st person (versus 3rd person) visual perspective in autobiographical memory, even after full remission. This study aimed to examine visual perspective in healthy never-depressed subjects presenting with either genetic or psychological vulnerability for depression. Sixty healthy participants performed the Autobiographical Memory Test with an assessment of visual perspective.

Association between triallelic polymorphism of the serotonin transporter and [18F]MPPF binding potential at 5-HT1A receptors in healthy subjects.

Previous [(11)C]WAY100-635 PET studies have demonstrated that the short (S) and long (L) alleles of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) were associated with distinct patterns of 5-HT(1A) receptor distribution in human. However, these studies reported discordant findings and did not take into account the recent description of two functional variants of the L allele (L(A)/L(G)). To further explore this issue, we investigated the triallelic functional polymorphism of the 5-HTTLPR in 38 healthy volunteers who underwent a [(18)F]MPPF PET study of 5-HT1A receptors.

A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD).

Atomoxetine is a specific inhibitor of the norepinephrine transporter (NET) that has demonstrated efficacy in the treatment of children with attention-deficit hyperactivity disorder (ADHD). We investigated whether polymorphisms in the NET/SLC6A2 gene may influence atomoxetine response in ADHD. Two independent cohorts of 160 and 105 ADHD children treated for 6 weeks with atomoxetine (0.

The TaqI A DRD2 polymorphism in type II alcohol dependence: a marker of age at onset or of a familial disease?

Cloninger's type II is a severe, early-onset, male-limited, and genetically influenced, impulsive form of alcoholism. Significant association has been reported between the A1 allele of the D2 dopamine receptor (DRD2) gene, substance misuse and personality traits of impulsivity and novelty seeking. We assessed the association between the TaqI A DRD2 gene polymorphism with Cloninger's typology and family history of alcohol abuse, which is thought to be more frequent in type II alcoholics.

Excess of transmission of the G allele of the -1438A/G polymorphism of the 5-HT2A receptor gene in patients with schizophrenia responsive to antipsychotics.

Background: The -1438A/G polymorphism of the 5-HT2A gene has been found to be associated with clinical response to clozapine and other second generation antipsychotics. Testing the impact of this marker on response to first generation antipsychotics (which have a lower affinity for the 5-HT2A receptor) provides the opportunity to help disentangling the two different roles that this polymorphism might have. A psychopharmacogenetic role should be detected only for antipsychotics with high affinity to the 5-HT2A receptor (therefore to second generation antipsychotics).

Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction.

Dysfunctions affecting the connections of basal ganglia lead to major neurological and psychiatric disorders. We investigated levels of mRNA for three neurexins (Nrxn) and three neuroligins (Nlgn) in the globus pallidus, subthalamic nucleus, and substantia nigra, in control conditions and after short-term exposure to cocaine. The expression of Nrxn2beta and Nlgn3 in the substantia nigra and Nlgn1 in the subthalamic nucleus depended on genetic background.

The short allele of the serotonin transporter promoter polymorphism influences relapse in alcohol dependence.

Aims: The short (S) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR) contributes to the risk of alcohol dependence and co-occurring clinical features. We studied the putative link between this allele and relapse.

Methods: 48 alcohol-dependent male patients were recruited and genotyped for the 5-HTTLPR.

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.

The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence.

Background: Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter (DAT1/SLC6A3) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence.

Methods: To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence.

The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia.

Neurobiological research suggests a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Genetics offer an opportunity to disentangle its involvement in the disease vulnerability vs an influence on antipsychotics' effects. The possible role of a tag SNP (the 1359G/A polymorphism) of the gene encoding the cannabinoid receptor type 1 (CNR1) in schizophrenia and/or therapeutic response to atypical antipsychotics was assessed in a cohort of 133 French schizophrenic patients compared to 141 normal control subjects.

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 leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight.

Gender-dependent regulation of G-protein-gated inwardly rectifying potassium current in dorsal raphe neurons in knock-out mice devoid of the 5-hydroxytryptamine transporter.

Agonists at G-protein-coupled receptors in neurons of the dorsal raphe nucleus (DRN) of knock-out mice devoid of the serotonin transporter (5-HTT(-/-)) exhibit lower efficacy to inhibit cellular discharge than in wild-type counterparts. Using patch-clamp whole-cell recordings, we found that a G-protein-gated inwardly rectifying potassium (GIRK) current is involved in the inhibition of spike discharge induced by 5-HT1A agonists (5-carboxamidotryptamine (5-CT) and (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT); 50 nM-30 microM) in both wild-type and 5-HTT(-/-) female and male mice. These effects were mimicked by 5'-guanylyl-imido-diphosphate (Gpp(NH)p; 400 microM) dialysis into cells with differences between genders.

Negative symptoms of schizophrenia could explain discrepant data on the association between the 5-HT2A receptor gene and response to antipsychotics.

Pharmacogenetic studies assessing the role of 5-HT(2A) receptor gene in antipsychotic efficacy yielded conflicting data. Phenotypical heterogeneity of schizophrenia might explain such discrepancies. For example, negative symptoms are known to reflect severity of illness and to restrain therapeutic response.

Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations.

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia.

The A9 allele of the dopamine transporter gene increases the risk of visual hallucinations during alcohol withdrawal in alcohol-dependent women.

Previous studies have found an association between the A9 allele (nine-copy repeat) of the dopamine transporter (DAT) gene and two complications of alcohol withdrawal, namely delirium tremens (DT) and alcohol withdrawal seizures (AWS). Most of these studies only included male alcohol-dependent patients. Even those that included a small proportion of women did not look at the effect of gender.

Serotonin transporter in substance P (neurokinin 1) receptor knock-out mice.

We recently demonstrated that mice lacking the gene for substance P (neurokinin 1) receptors (NK1-/-) show improved cortical dialysate serotonin (5-HT) responses to paroxetine [J. Neurosci. 21 (2001) 8188].

Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations.

Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients.