E. Pegg

CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms

Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n=1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5′ end of the CNR1 gene significantly interacts with the 3′ end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene × environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression––and probably also for co-morbid psychiatric conditions such as substance use disorders––through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.

Variations in the cannabinoid receptor 1 gene predispose to migraine

In animal models endogenous cannabinoids have an inhibitory effect on trigeminovascular activation through the cannabinoid receptor 1 (CB1), although there is no evidence of the potential role of CB1 in human migraine. In this study we applied single marker association and haplotypic trend regression analysis to investigate the relationship between the CB1 gene (CNR1) and headache with migraine symptoms (nausea, photophobia and disability, measured by the ID-migraine questionnaire). We identified our controls (CO=684) as those who have not reported ID-migraine symptoms at all and defined migraine headache sufferers (M=195) as those who reported all three symptoms. The CNR1 was covered by 10 SNPs located throughout the gene based on haplotype tagging (htSNP) and previous literature. Our results demonstrated a significant haplotypic effect of CNR1 on migraine headaches (p=0.008, after permutation p=0.017). This effect was independent of reported depression or drug/alcohol abuse although using neuroticism in the analysis as covariant slightly decreased this association (p=0.027, permutated p=0.052). These results suggest a significant effect of CNR1 on migraine headaches that might be related to the alteration of peripheral trigeminovascular activation. In addition, this is the first study to demonstrate the effectiveness of using trait components combinations to define extreme phenotypes with haplotype analysis in genetic association studies for migraine. However, further studies are needed to elucidate the role of CNR1 and the cannabinoid system in migraine.

PW07-02 Self-reported rumination as trait marker for depression: Evidence from functional neuroimaging

Background Research using fMRI indicates that sustained limbic activity is linked to processing negative words and self-reported rumination in currently depressed individuals. It is unknown whether this is also present in remitted depressed individuals. We tested the hypothesis that a tendency to ruminate constitutes a trait for depression by using a standard covert fMRI emotional task face in previously and never depressed volunteers and postulated that high rumination scores would correlate with activity in brain areas previously associated with depression. Methods 37 controls (25 female) and 30 remitted depressed (RD, 22 female) were enrolled. Volunteers completed the Ruminative Responses Scale (RRS) and underwent fMRI scanning using a standard covert fMRI emotional task faces. Significance level was set at p Results With RRS score controlled for RD showed reduced subcortical and limbic activity to sad and fearful faces compared to controls. Correlations between RRS scores and neural activity in all participants and control participants alone were very limited. However, in RD, RRS score was negatively correlated with neural response to happy faces and positively correlated with neural response to sad and fearful faces, in cortical and limbic regions associated with depression (hippocampus, thalamus, caudate, insula and cingulate gyrus). Conclusion The results suggest that reduced limbic activity is associated with remission, possibly as a maintenance mechanism. However, within the remitted group the more ruminative participants show greater response in these areas to negative stimuli, and less to positive stimuli. This could be a neurobiological marker for risk of relapse.

P.1.a.007 Decision-making behaviour is influenced by tryptophan hydroxylase 2 gene

Introduction: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of the neurotransmitter serotonin (5-HT). There are two main subtypes, the TPH2 subtype which is involved in neuronal serotonin synthesis and the TPH1 subtype which is involved in serotonin synthesis in the periphery. Polymorphisms in the TPH2 gene and distinct haplotypes (combinations of single nucleotide polymorphisms (SNPs) which are inherited together) with functional effects on the TPH enzyme activity may represent risk factors for serotonergic system related psychiatric disorders. However, genetic studies of TPH2 related to depression, schizophrenia, alcoholism, drug abuse, aggression and suicidality have produced conflicting results. One possible explanation of this is that TPH2 function might relate to a more basic behavioural feature, or endophenotype, involved in many psychiatric disorders. Decision making may be defined as the ability to select an advantageous response from a range of available options. Impaired decision making, attributed to a 5-HT deficit in orbitofrontal cortex (OFC), is one candidate endophenotype for many psychiatric conditions. Previous studies demonstrated that rapid dietary tryptophan depletion – leading to reduced central serotonin function – altered the decision-making of healthy volunteers. In our study, we tested the hypothesis that TPH2 haplotype will affect decision making, in a large sample using a simple paper-pencil task. Methods: From the NewMood population study cohort we present interim data on 864 subjects who completed a pencil and paper decision making task, the 53-item Brief Symptom Checklist and for whom we have TPH2 genetic haplotype data. The task consisted of choosing between two ‘wheel of fortunelike’ alternatives: ‘A’ which provided a smaller but more likely ‘win’ and ‘B’ which gave a ‘win’ 2 times the amount with lower probability that was systematically varied. We used a repeated measure design with 4 different probability levels of winning on ‘A’. The probability of winning on ‘B’ at which the subjects valued the two trials equally (indifference point) was determined as a measure of willingness to take a risk. The HaploView software package was employed to identify htSNPs based on the genotype data of CEPH population (International HapMap Project). The chosen SNPs were genotyped using Sequenom’s massarray technology and haplotypes were generated by HelixTree. Results: TPH2 haplotypes (p = 0.003) and Anxiety scores (p = 0.001) had an independent significant effect on decision making, with more anxious subjects making less risky choices. There was no interaction between TPH2 haplotypes and Anxiety scores. Depression scores had no effect on decision making. Discussion: This study supports the role of TPH2 gene, and the 5-HT system, in risk taking behaviour. This genetic effect is independent of mood state and might be an additive factor contributing to psychiatric disorders.