A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment

Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further

Therapygenetics: using genetic markers to predict response to psychological treatment for mood and anxiety disorders

Considerable variation is evident in response to psychological therapies for mood and anxiety disorders. Genetic factors alongside environmental variables and gene-environment interactions are implicated in the etiology of these disorders and it is plausible that these same factors may also be important in predicting individual differences in response to psychological treatment. In this article, we review the evidence that genetic variation influences psychological treatment outcomes with a primary focus on mood and anxiety disorders. Unlike most past work, which has considered prediction of response to pharmacotherapy, this article reviews recent work in the field of therapygenetics, namely the role of genes in predicting psychological treatment response. As this is a field in its infancy, methodological recommendations are made and opportunities for future research are identified

Catechol-O-methyltransferase (COMT) val158met Polymorphism as a Risk Factor for PTSD After Urban Violence

PTSD is a psychiatric disorder that requires a traumatic event as diagnostic criteria. Brazil has high rates of violence, and it is expected that urban victims of violence would be at risk to the development of PTSD. Studies have associated the COMT val158met polymorphism with diminished stress resilience, reduced ability to extinguish conditioned fear, and the development of PTSD after multiple traumatic experiences. the aim of this study was to identify, in a case-control study, whether the val158met polymorphism (rs4860) is associated with the development of PTSD in a group of victims of urban violence. To our knowledge, this is the first study that examines the association between PTSD and urban violence. the polymorphism of COMT in PTSD patients (n = 65) as well as in victims of violence without PTSD (n = 34) and in a community control group (n = 335) were genotyped. We found a significant relationship between the met allele (p < 0.02) and PTSD among cases (PTSD+)and victims of violence without PTSD (PTSD-; OR 2.57) and between cases and community control group (p < 0.003) Further analysis with larger samples and another ethnic group should be necessary to confirm our findings.Fundacao de Amparo a Pesquisa Estado de São PauloCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo, Dept Psiquiatria, Fac Med, BR-04023061 São Paulo, SP, BrazilKings Coll London, Inst Psychiat, Hlth Serv & Populat Res Dept, London WC2R 2LS, EnglandUniversidade Federal de São Paulo, Dept Psiquiatria, Fac Med, BR-04023061 São Paulo, SP, BrazilFundacao de Amparo a Pesquisa Estado de São Paulo: 2004/15039-0Web of Scienc

Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex

The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (450 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC

Comprehensive interrogation of CpG island methylation in the gene encoding COMT, a key estrogen and catecholamine regulator

BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme has been widely studied due to its multiple roles in neurological functioning, estrogen biology, and methylation metabolic pathways. Numerous studies have investigated variation in the large COMT gene, with the majority focusing on single nucleotide polymorphisms (SNPs). This body of work has linked COMT genetic variation with a vast array of conditions, including several neurobehavioral disorders, pain sensitivity, and multiple human cancers. Based on COMT’s numerous biological roles and recent studies suggesting that methylation of the COMT gene impacts COMT gene expression, we comprehensively interrogated methylation in over 200 CpG dinucleotide sequences spanning the length of the COMT gene. METHODS: Using saliva-derived DNA from a non-clinical sample of human subjects, we tested for associations between COMT CpG methylation and factors reported to interact with COMT genetic effects, including demographic factors and alcohol use. Finally, we tested associations between COMT CpG methylation state and COMT gene expression in breast cancer cell lines. We interrogated >200 CpGs in 13 amplicons spanning the 5’ UTR to the last exon of the CpG dinucleotide-rich COMT gene in n = 48 subjects, n = 11 cell lines and 1 endogenous 18S rRNA control. RESULTS: With the exception of the CpG island in the 5’UTR and 1(st) exon, all other CpG islands were strongly methylated with typical dynamic ranges between 50-90%. In the saliva samples, methylation of multiple COMT loci was associated with socioeconomic status or ethnicity. We found associations between methylation at numerous loci and genotype at the functional Val( 158 )Met SNP (rs4680), and most of the correlations between methylation and demographic and alcohol use factors were Val( 158 )Met allele-specific. Methylation at several of these loci also associated with COMT gene expression in breast cancer cell lines. CONCLUSIONS: We report the first comprehensive interrogation of COMT methylation. We corroborate previous findings of variation in COMT methylation with gene expression and the Val( 158 )Met genotype, and also report novel associations with socioeconomic status (SES) and ethnicity at several methylated loci. These results point to novel mechanisms for COMT regulation, which may have broad therapeutic implications