Mariliis Vaht

Serotonin transporter gene promoter polymorphism (5-HTTLPR) and alcohol use in general population: interaction effect with birth cohort

Rationale and objectivePrevalence of alcohol use is markedly influenced by socioeconomic conditions and is therefore subject to cohort effects. The common genetic variation 5-HTTLPR (serotonin transporter gene-linked polymorphic region) has been related to several aspects of alcohol use and addiction but with mixed results, probably due to different environmental interaction effects. We aimed at assessing whether the association between alcohol use and 5-HTTLPR genotype is subject to cohort effects as birth cohorts may be raised in significantly different environments.MethodsWe used the database of the Estonian Children Personality Behaviour and Health Study (beginning in 1998). Cohorts of initially 9-year-old (recalled at ages 15 and 18) and 15-year-old (recalled at ages 18 and 25) children provided self-reports on their alcohol use in all data collection waves (complete data available n = 1,075).ResultsA significant genotype × gender × cohort interaction effect on the age of consuming the first alcoholic drink was found [F(2, 1,063) = 7.2, p < 0.001]. Females with the s/s genotype in the older cohort were the latest experimenters with alcohol, while the s/s females of younger cohort had tried alcohol earlier than any other group. In males, there was no significant cohort × genotype interaction, but the 5-HTTLPR genotype was associated with alcohol use, the s/s subjects reporting the highest consumption.ConclusionExpression of genetic vulnerability to alcohol use is influenced by birth cohort effects. The 5-HTTLPR genotype is associated with alcohol consumption in general population, but the effect depends on gender and birth cohort.

Effect of tryptophan hydroxylase-2 gene polymorphism G-703 T on personality in a population representative sample

The tryptophan hydroxylase-2 gene (TPH2) is coding for the key enzyme of serotonin (5-HT) synthesis in the brain and has been associated with a number of psychiatric conditions. A functional variation in the TPH2 gene (G-703T, rs4570625) has been found to affect anxiety-related personality; however, information is very limited regarding the five factor model (FFM) personality traits. We have examined the association of the TPH2 G-703T polymorphism with FFM personality traits, and the possible modulation by the functional variation in the serotonin transporter gene (5-HTTLPR) in a large longitudinal population representative sample. The FFM personality traits were assessed in both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n=742) and 18 (n=834). Significant association of the TPH2 genotype with Neuroticism and Conscientiousness was found at age 15, and with Extraversion and Conscientiousness at age 18. Participants with the T/T genotype scored significantly lower on Neuroticism and higher on Conscientiousness and Extraversion scales. In addition, a gene×gene interaction effect on Conscientiousness was revealed: the TPH2 genotype effect was evident only in the 5-HTTLPR S-allele carriers. These results provide further evidence on the possible role of genetic variations in 5-HT neurotransmission on development of personality traits, and suggest a functional interaction between two key proteins in the 5-HT-ergic system.

A Functional Vesicular Monoamine Transporter 1 (VMAT1) Gene Variant Is Associated with Affect and the Prevalence of Anxiety, Affective, and Alcohol Use Disorders in a Longitudinal Population-Representative Birth Cohort Study

Background: Inter-individual differences in the monoaminergic systems have been shown to moderate the risk for a lifetime history of anxiety, affective, and alcohol use disorders. A common single nucleotide polymorphism in the vesicular monoamine transporter 1 gene (VMAT1 rs1390938 G/A; Thr136Ile) has been reported as functional in vitro and associated with bipolar disorder and anxiety. We aimed at assessing the association between the VMAT1 genotype, affect, and affect-related psychiatric disorders in a longitudinal population-representative study. Methods: We used the database of the Estonian Children Personality Behaviour and Health Study (beginning in 1998). Cohorts of initially 9- (recalled at ages 15 and 18 years, n=579) and 15- (recalled at ages 18 and 25 years; n=654) year-old children provided self-reports on impulsivity, anxiety, depressiveness, neuroticism, and alcohol use. In addition, psychiatric assessment based on DSM-IV was carried out in the older cohort at age 25 years. Results: Subjects homozygous for the less prevalent A (136Ile) allele reported lower maladaptive impulsivity, state and trait anxiety, depressiveness, and neuroticism and were less likely to have been diagnosed with an affective, anxiety, and/or alcohol use disorder by young adulthood. While in the younger cohort alcohol use started at younger age, this birth cohort effect was dependent on genotype: only G allele carriers and in particular the GG homozygotes started alcohol use earlier. Conclusions: VMAT1 rs1390938/Thr136Ile is associated with mood, personality, and alcohol use in the general population. Subjects homozygous for the “hyperfunction” allele (AA; Ile/Ile) appear to be more resilient to these disorders.

Oxytocin receptor gene variation rs53576 and alcohol abuse in a longitudinal population representative study.

BACKGROUND Oxytocin is an important regulator of social relationships and has been implicated in development of substance use and addiction. We examined the association of a variance in the oxytocin receptor gene (OXTR rs53576 polymorphism) with alcohol use in a population-representative sample, and potential moderation by social functioning. METHODS The analysis was carried out on the older birth cohort of the longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS), a cohort of initially 15 years old children (original n=593) recalled at ages 18 and 25. In all data collection waves the participants reported the frequency of consuming alcoholic beverages. Psychiatric interview was carried out at age 25 to assess the lifetime prevalence of substance use disorders. Adverse social interactions with teachers, classmates and family members were self-reported at ages 15 and 18. The minor (A) allele frequency was 0.37. RESULTS Males homozygous for the A allele (suggested to be associated with less efficient oxytocinergic functioning) were more frequent alcohol consumers at ages 15 and 18 and also more likely to have had alcohol abuse or addiction by age 25 compared to male G allele carriers. Alcohol use was not associated with the OXTR genotype in females. Both male and female AA homozygotes who had reported less favourable relations with their teachers at age 15 more likely had alcohol use disorder. CONCLUSIONS OXTR rs53576 polymorphism is associated with alcohol use and prevalence of alcohol use disorders in males, and this may be moderated by inferior interpersonal relationships.

Variants of TPH2 interact with fast visual processing as assessed by metacontrast

Sensitivity to threatening or otherwise unpleasant visual stimuli has become a widely used measure of potential vulnerability/resilience. Basically, experiments using this strategy present brief stimuli, often followed by a mask, and individuals’ sensitivity is measured. However, it has not been asked whether the individual differences in threat detection or adaptive resilience associated with genetic variability-related endophenotypes might be just a function of some basic visual functions involved in processing and reporting brief visual stimuli without any emotional content. Effects attributed to emotional processing may be confounded by variability in simple basic visual skills. However, if simple visual skills are variable depending on common genetic variability, simple perceptual tests of screening for genetic risks can be developed. In a sample of normal human individuals, we studied the effects of a single nucleotide polymorphism (rs4570625) in the gene that encodes the rate-limiting enzyme in serotonin synthesis, TPH2, on metacontrast masking. Visual discrimination of target shapes that were incongruent with mask shapes was poorer in G homozygotes (typically considered more resilient individuals) compared with T-allele carriers and this effect was influenced by participants’ sex. Implications for the development of psychophysical testing-based methods of screening for vulnerability/resilience in relation to the pathology of the serotonergic system-related dysfunction are considered.

A functional neuregulin-1 gene variant and stressful life events: Effect on drug use in a longitudinal population-representative cohort study:

Background: The neuregulin 1 gene is a susceptibility gene for substance dependence. A functional polymorphism (SNP8NRG243177/rs6994992; C/T) in the promoter region of the brain-specific type IV neuregulin-1 gene (NRG1) has been associated with psychiatric disorders (e.g. schizophrenia and bipolar disorder) that often present higher odds of smoking, alcohol and illicit drug use. This study assessed the association of the NRG1 genotype with drug use and possible interaction with stressful life events (SLEs). Methods: The database of the Estonian Children Personality Behaviour and Health Study (beginning in 1998) was used. Cohorts of children initially 9 years old (n=583; followed up at 15 and 18 years) and 15 years old (n=593; followed up at 18 and 25 years) provided self-reports on alcohol, tobacco and illicit substance use and SLEs. Psychiatric assessment based on DSM-IV was carried out on the older birth cohort at age 25 to assess the lifetime presence of substance use disorders. NRG1 rs6994992 was genotyped in all participants by TaqMan® Pre-Designed SNP Genotyping Assay on the Applied Biosystems ViiA™ 7 Real-Time PCR System. The minor (T) allele frequency was 0.37. Results: NRG1 rs6994992 C/C homozygotes, especially those who had experienced more SLEs, were more likely to develop alcohol use disorders by young adulthood, were generally more active consumers of tobacco products, and had more likely used illicit drugs. In T allele carriers, SLEs had a negligible effect on substance use. Conclusions: In humans, NRG1 genotype is associated with substance use, and this relationship is moderated by adverse life events, with a gain-of-function allele being protective.

Stressful life events increase aggression and alcohol use in young carriers of the GABRA2 rs279826/rs279858 A-allele

Research of GABRA2 gene in alcohol use and impulse control suggests its role in aggressive behaviour. The purpose of the present study was to examine the effects of GABRA2 genotype and stressful life events on aggressive behaviour, alcohol use frequency and occurrence of alcohol use disorder in a population representative sample of adolescents followed up from third grade to 25 years of age. The sample consisted of the younger cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study. Aggressive behaviour was rated with the activity scale of af Klinteberg, Illinois Bully Scale and Buss-Perry Aggression Questionnaire. Stressful life events and alcohol use were self-reported. Life history of aggression and lifetime occurrence of psychiatric disorders were estimated in a structured interview. The sample was genotyped for GABRA2 rs279826 and rs279858 polymorphisms that are in strong linkage disequilibrium and yielded very similar findings: Higher number of stressful life events reported at age 15 was associated with increased fighting in A-allele carriers, but not in GG homozygotes. At age 25, A-allele carriers with more stressful life events scored higher on physical aggression than those with less stress, and this was also observed regarding life history of aggression. A-allele carriers exposed to higher stress had consumed alcoholic beverages more frequently at age 15, and by age 25, they had alcohol use disorder with higher prevalence. The results of the present study suggest that the GABRA2 genotype interacts with stress in young people with impact on the development of alcohol use and aggressive behaviour.

Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety

BACKGROUND Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. METHODS We used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts. RESULTS The TT homozygous males reported less aggressive behaviour in the Life History of Aggression interview at age 25. They also had significantly lower scores in Illinois Bully Scale peer reports, and less ADHD symptoms rated by teachers both at ages 9 and 15. The TT homozygotes of both sexes had the lowest Maladaptive Impulsivity at ages 18 and 25, and the highest Adaptive Impulsivity at age 25. The TT homozygotes also had low depressiveness and trait anxiety by age 25, and the odds ratio for the prevalence of anxiety disorders was 9.38 for the G-allele carriers. LIMITATIONS The main limitation of the study is the naturally occurring low number of subjects with the TT genotype. CONCLUSIONS Subjects with the TPH2 rs4570625 TT genotype, especially males, exhibit less aggression and a favourable impulsivity profile, and develop anxiety disorders by young adulthood less often.

Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity: Dependence on cholesterol levels.

BACKGROUND Impulsivity is multidimensional: Low impulse control may result in behavioural disorders, but acting on the spur of moment may also be advantageous. Previous studies have shown negative associations between different facets of impulsivity and serotonergic function. Other investigations have found negative correlations between serum lipid levels and impulsivity. METHODS We have investigated whether the functional polymorphism -1438A/G in the serotonin 5-HT2A receptor gene (HTR2A) is associated with impulsivity levels and whether there is any interaction with serum lipid levels. This analysis was based on data of the population-representative Estonian Children Personality Behaviour and Health Study at age 25. Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. RESULTS Subjects with the A/A genotype of the HTR2A -1438A/G polymorphism had higher scores of Maladaptive impulsivity, but not Adaptive impulsivity. In females, high LDL and total cholesterol levels increased the genotype effect. In males, in the highest quartile of total or LDL cholesterol the genotype effect was altered, with G/G homozygotes having the highest Maladaptive impulsivity levels. LIMITATIONS Only one cohort of the European Youth Heart Study (EYHS) was used in the current study and impulsivity measures were self-reported. CONCLUSIONS Our results do not support the notion that low cholesterol levels universally lead to higher impulsivity, but it was found that high total and LDL cholesterol levels moderate the effect of the HTR2A gene promoter polymorphism. This suggests that future studies on impulsivity need to consider the interaction of serotonergic measures with the whole range of cholesterol levels.

Overnight retention of emotional memories is influenced by BDNF Val66Met but not 5-HTTLPR

HighlightsBDNF Val66Met influences overnight emotional memory retention.Greater post‐sleep memory for emotional images in Met carriers.Longer REM sleep duration predicts greater emotional memory for Met carriers.No emotion‐specific effects of 5‐HTTLPR on overnight memory retention. Abstract Emotional memory may be modulated by BDNF Val66Met and 5‐HTTLPR polymorphisms. However, the influence of these genetic variants on the overnight retention of emotional memories has not been investigated in humans. Thirty‐six healthy female students were selected to participate in this study based on 5‐HTTLPR genotype status (L’/L’, L’/S’, S’/S’). Participants were also genotyped for BDNF Val66Met (Val/Val, Met carriers). We measured recognition performance for positive, neutral and negative images before and after overnight sleep. We found a significant interaction between BDNF Val66Met genotype group and image valence on post‐sleep recognition performance. This interaction was driven by greater memory for negative and positive images, relative to neutral images, in Met carriers. We also found that longer Rapid Eye Movement (REM) sleep duration predicted greater post‐sleep recognition performance for negative images in Met carriers, but not in Val homozygotes. We observed no influence of 5‐HTTLPR polymorphisms on post‐ sleep recognition performance for positive, neutral or negative images. Our findings support a modulatory role for BDNF Val66Met in overnight emotional memory retention in females. We discuss the implications of this finding for understanding the influence of BDNF Val66Met on depression vulnerability.