Functional promoter polymorphism of the neuronal isoform of tryptophan hydroxylase (Tph2) in suicide

The association between suicide and G-703T polymorphism of the tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin, was studied in a sample of 291 suicide victims and 280 healthy subjects of Croatian origin. No significant differences were found between the groups. Obtained results do not support involvement of the investigated polymorphism in the susceptibility to suicide completion

Serotonin-Related Gene Polymorphisms and Asymptomatic Neurocognitive Impairment in HIV-Infected Alcohol Abusers

HIV-infected individuals continue to experience neurocognitive deterioration despite virologically successful treatments. While the cause remains unclear, evidence suggests that HIV-associated neurocognitive disorders (HAND) may be associated with neurobehavioral dysfunction. Genetic variants have been explored to identify risk markers to determine neuropathogenesis of neurocognitive deterioration. Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life and HIV risk-taking behaviors. Single nucleotide polymorphisms in the SLC6A4, TPH2, and GALM genes may affect the activity of serotonin and increase the risk of HAND. The present study explored the relationship between SLC6A4, TPH2, and GALM genes and neurocognitive impairment in HIV-infected alcohol abusers. A total of 267 individuals were genotyped for polymorphisms in SLC6A4 5-HTTLPR, TPH2 rs4570625, and GALM rs6741892. To assess neurocognitive functions, the Short Category and the Auditory Verbal Learning Tests were used. TPH2 SNP rs4570625 showed a significant association with executive function in African American males (odds ratio 4.8, 95% CI, 1.5–14.8; ). Similarly, GALM SNP rs6741892 showed an increased risk with African American males (odds ratio 2.4, 95% CI, 1.2–4.9; ). This study suggests that TPH2 rs4570625 and GALM rs6741892 polymorphisms may be risk factors for HAND

Gender Moderates the Association between 5-HTTLPR and Decision-making under Ambiguity but Not under Risk

Decisions made under ambiguity may involve a different genetic architecture than those made under risk. Because gender moderates the effect of genetic polymorphisms on serotonin function and because there are gender differences in decision-making, the present study examined potential gender moderation of associations between polymorphisms in important serotonin system candidate genes (serotonin transporter [SLC6A4] and tryptophan hydroxylase-2 [TPH2]) and performance on a decision-making task (Iowa Gambling Task, IGT) in healthy, adults (N = 188; 62% women). Subjects were genotyped for the well-studied SLC6A4 promoter variant 5-HTTLPR and a TPH2 single nucleotide polymorphism in intron-8 (rs1386438). Genotype at rs1386438was not associated with performance on the IGT. A significant gender by 5-HTTLPR genotype interaction effect was detected when decision-making was under ambiguity (i.e., the first block of 20 choices) but not under risk (blocks 2–5). Performance on the first block of 20 choices was not correlated with performance on subsequent blocks, supporting the interpretation that early performance on the IGT indexes decision-making under ambiguity, while performance on blocks 2–5 indexes decision-making under risk. These findings suggest that decision-making under ambiguity and risk may have different genetic architectures and that individual differences in decision-making under ambiguity are associated with genetic variation in SLC6A4

The role of tryptophan and tyrosine in executive function and reward processing

The serotonergic precursor tryptophan and the dopaminergic precursor tyrosine have been shown to be important modulators of mood, behaviour and cognition. Specifically, research on the function of tryptophan has characterised this molecule as particularly relevant in the context of pathological disorders such as depression. Moreover, a large body of evidence has now been accumulated to suggest that tryptophan may also be involved in executive function and reward processing. Despite some clear differentiation with tryptophan, the data reviewed in this paper illustrates that tyrosine shares similar functions with tryptophan in the regulation of executive function and reward, and that these processes in turn, rather than acting in isolation, causally influence each other

The Influence of Gene Environment Interaction on the Risk of Cognitive Impairment: Reducing Sexual Risk Behaviors and Alcohol Use in HIV-infected Adults

Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life, antiretroviral adherence, and HIV risk behaviors. Several factors have been suggested including the role of genetics in relation to HIV disease progression. This dissertation aimed to determine whether genetic differences in HIV-infected individuals were correlated with impaired memory, cognitive flexibility and executive function and whether cognitive decline moderated alcohol use and sexual transmission risk behaviors among HIV-infected alcohol abusers participating in an NIH-funded clinical trial comparing the efficacy of the adapted Holistic Health Recovery Program (HHRP-A) intervention to a Health Promotion Control (HPC) condition in reducing risk behaviors. A total of 267 individuals were genotyped for polymorphisms in the dopamine and serotonin gene systems. Results yielded significant associations for TPH2, GALM, DRD2 and DRD4 genetic variants with impaired executive function, cognitive flexibility and memory. SNPs TPH2 rs4570625 and DRD2 rs6277 showed a risk association with executive function (odds ratio = 2.5, p = .02; 3.6, p = .001). GALM rs6741892 was associated with impaired memory (odds ratio = 1.9, p = .006). At the six-month follow-up, HHRP-A participants were less likely to report trading sex for food, drugs and money (20.0%) and unprotected insertive or receptive oral (11.6%) or vaginal and/or anal sex (3.2%) than HPC participants (49.4%,

Association Analysis of the Tryptophan Hydroxylase 2 Gene Polymorphisms in Patients with Methamphetamine Dependence/Psychosis

There is a growing evidence that serotoninergic systems modulate dopaminergic neurotransmission. We analyzed the association between the variations in the brain tryptophan hydroxylase 2 (TPH2) gene, a rate limiting enzyme for serotonin biosynthesis, and methamphetamine (METH) dependence/psychosis in a Japanese population. We found ten single nucleotide polymorphisms (SNPs) and two polynucleotide polymorphisms in TPH2 gene exons and exon-intron boundaries. A total of 162 patients and 243 controls were used for the association analysis between these polymorphisms and METH dependence/psychosis. No significant differences were observed in either genotypic or allelic frequencies between METH dependent/psychotic patients and controls. A global test of differentiation among samples based on haplotype frequencies showed no significant association. With respect to latency of psychosis, prognosis of psychosis, and spontaneous relapse, we found no significant association with these SNPs. These results suggest that the TPH2 gene variants may not be a factor in vulnerability to METH dependence/psychosis

Serotonin System Gene Polymorphisms Are Associated with Impulsivity in a Context Dependent Manner

Impulsivity is a risk factor for adverse outcomes and characterizes several psychiatric disorders and risk for suicide. There is strong evidence that genetic variation influences individual differences in impulsivity, but the details are not yet understood. There is growing interest in better understanding the context dependency of genetic effects that is reflected in studies examining gender specificity, gene × environment interaction and epistasis (gene-gene interaction). In a cross-sectional study we examined whether polymorphisms in six serotonin system candidate genes and the experience of early life trauma (age 0–12) were associated with individual differences in impulsivity in a nonclinical sample of Caucasian university students (N = 424). We specifically tested potential gender specific, gene-gene, and gene × environment (early life trauma) effects. In our main analyses with Barratt Impulsiveness Scale (BIS-11) total score, there were significant (i.e., p \u3c .01 and False Discovery Rate \u3c .10) interactions between (1) gender and TPH2 (rs1386483) genotype; (2) gender and HTR2A (rs6313) genotype; and epistatic interactions among (3) 5-HTTLPR and MAOA uVNTR; (4) 5-HTTLPR and rs6313 and (5) HTR1B (rs6296) and rs6313 genotypes. Our results strongly support the explicit investigation of context-dependent genetic effects on impulsivity and may help to resolve some of the conflicting reports in the literature

Depressiooni ja ärevusega seotud geenivariandid: mõju isiksuseomadustele ja tervistmõjustavale käitumisele

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Varasemate uuringute põhjal on teada, et mõned isiksuseomadused suurendavad depressiooni tekkimise riski. Nii isiksuseomadustel kui ka depressioonil on aga tugev pärilik taust ja osa geneetilisest alusest arvatakse neil olevat ühine. Kummagi fenotüübi geneetilist ülesehitust ei ole veel suudetud tuvastada. Käesoleva väitekirja eesmärgiks oli uurida suurel rahvastiku suhtes representatiivsel valimil, kuidas on seotud neurotransmissiooni mõjustavad depressiooni kandidaatgeenide variandid 5-HTTLPR, BDNF Val66Met, COMT Val158Met ja TPH2 G-703T isiksuseomadustega. Lisaks uurisime ka geenidevahelisi interaktsioone, vanuse ja soo mõju ning seoseid teiste tervise ja heaolu teguritega. Leidsime, et kõik nimetatud kandidaatgeenid tõepoolest mõjutavad isiksuseomadusi rahvastikus. COMT genotüüp avaldab mõju Neurootilisusele, ehk kalduvusele liigselt muretseda ja ärevust tunda. BDNF ja TPH2 mõjutavad aga Meelekindlust, inimese kalduvust olla kohusetundlik, täpne ja distsipliineeritud. Ilmnes ka 5-HTTLPR polümorfismi moduleeriv roll genotüübi ja Meelekindluse seostes. Samuti leidsime, et nii TPH2 kui COMT genotüüpide mõju Neurootilisusele oli sõltuv uuritavate vanusest. Kuigi me ei leidnud nimetatud geenivariantide seoseid ärevus- ja meeleoluhäiretega, peegeldub mõju isiksusele ka teistes inimese tervise ja heaoluga seotud tegurites. Näiteks BDNF polümorfism avaldab mõju söömishäirete sümptomaatika tekkimisel ning COMT mõjutab depressiivsuse taset, haridusteed ja hinnanguid sotsiaalmajanduslikule staatusele. Käitumisgeneetika valdkonna ummikseis isiksuseomaduste geneetiliste aluste tuvastamisel viitab erinevatele moduleerivatele mõjuteguritele geeniefektide avaldumisel. Väitekirjas käsitletud suure rahvastikupõhise uuringu tulemuste põhjal rõhutame soo, vanuse ja geenidevahelise interaktsiooni arvestamise olulisust genotüüpide mõju uurimisel väga mitmetahulistele fenotüüpidele.Previous findings have indicated that some personality traits are increasing the risk for depression. Personality traits and depression are both to a significant extent heritable and are considered to share some of the genetic components. Unraveling the genetic basis of these phenotypes has proven to be difficult. The purpose of this dissertation was to study the effects of several depression-related gene variants, 5-HTTLPR, BDNF Val66Met, COMT Val158Met and TPH2 G-703T, on personality traits in a large population representative sample. In addition, we aimed to study gene × gene interactions, time and sex as possible modulators, and furthermore, to assess if there are any genotype effects on other health-related behaviours. Indeed, we found that all candidate genes under investigation had influence on personality traits. The COMT genotype was affecting Neuroticism, a trait for excessive worrying and anxiety. The main effects of BDNF and TPH2 gene variants were on Conscientiousness, a trait for dutifulness, precision and self-discipline. In addition, these genotype effects on Conscientiousness were modulated by the 5-HTTLPR polymorphism. Also we found the effects of TPH2 and COMT on Neuroticism to be age-dependent. Although we did not find any genotype effects on the history of mood and anxiety disorders, there were associations with health-related behaviour. We found the BDNF polymorphism to affect the emergence of eating disorder symptoms and COMT polymorphism to influence depressiveness, educational attainment, and also socioeconomic status assessment. The difficulties in unraveling the genetic foundations of personality traits suggest a large number of additional factors, which may modulate the emergence of genotype effects. With these results on a large population representative study, we highlight the significance of considering time, sex and gene × gene interactions as possible modulators of genotype effects

Startle response related genes

The startle reaction (also known as the startle response, the startle reflex, or the alarm reaction) is the psychological and physiological response to a sudden unexpected stimulus, such as a flash of light, a loud noise (acoustic startle reflex), or a quick movement near the face. Abnormalities of startle response have been observed in many stress-related mental disorders, such as schizophrenia and post-traumatic stress disorder (PTSD). However, the molecular mechanisms of startle in stress-associated conditions – for example, whether the startle reaction is associated with any gene variance – is still unknown. In this paper, we will carry out a systematic review by retrieving, assessing, and combining, when applicable, individual studies investigating association of the molecular variation of candidate gene with the startle response. The systematic review is based on the search for numerous publications using the keywords ‘‘startle gene’’ on September 15, 2010 using PubMed, which comprises more than 20 million citations for biomedical literature from MEDLINE and life science journals. A total of 486 publications regarding genes associated with startle have been obtained and reviewed here. There are fewer than 20 publications associating genes with the startle response between 1979, when the first valuable paper was published, and 1999. However, publications have dramatically increase from 2001 and reaches over 70 in 2009. We have characterized them into three categories: startle-associated gene studies in humans, in animals, as well as in both human and animals. This review of research strategy may provide the information for identifying a biomarker for startle response, with the objective of translating research into clinical utility: diagnosis and treatment of stress-induced mental disorders

COCAINE DEPENDENCE: THE ROLE OF SEROTONIN GENES IN

Animal studies have shown that behavioral responses to cocaine-related cues are altered by serotonergic medications. The effects of pharmacological agents on serotonin receptors 2a (5-HT2A) and 2c (5-HT2C), have yielded results suggesting that selective 5-HT2A antagonists and 5-HT2C agonists promote the disruption of cocaine-associated memories. One measure of cocaine related cues in humans is attentional bias, in which cocaine dependent individuals show greater response latency for cocaine related words than neutral words. Data from our laboratory shows that cocaine dependent subjects have altered attentional bias compared to controls. The purpose of this thesis was to investigate the role of the serotonin system in attentional bias and impulsivity in cocaine dependent individuals. We focused on the serotonin transporter, serotonin receptors 2A and 2C and tryptophan hydroxylase 1 and 2 (TPH1 and TPH2). We predicted that attentional bias and impulsivity would be higher in cocaine dependent individuals who had lower serotonin function. In the current study, we found a significant association between TPH2 genotype and attentional bias for the second block of the cocaine Stroop task. There was also a significant association between average attentional bias and HTTLPR genotype in the cocaine dependent individuals. The HT2C receptor genotype and attentional bias in our study sample also showed a significant difference. We did not find a significant difference between the serotonin 2A receptor variants or the TPH1 variants and attentional bias in the cocaine dependent group. In conclusion, the current study suggests that serotonergic medications should be utilized as pharmacotherapeutic treatment for cocaine addiction. Our results indicate that TPH2, the serotonin transporter and 2C receptor should be targeted in such a way as to modulate both, leading to increased synaptic serotonin function