Kariina Laas

A functional NPSR1 gene variant and environment shape personality and impulsive action: A longitudinal study

Neuropeptide S and its receptor NPSR1 are involved in the regulation of arousal, attention and anxiety. We examined whether the NPSR1 gene functional polymorphism Asn107Ile (rs324981, A>T) influences personality, impulsivity, and attention-deficit/hyperactivity disorder (ADHD)-related symptoms in a population-representative sample, and whether any eventual associations depend on age, sex, family relations and stressful life events (SLE). We used self-reports or teachers’ ratings for both the younger (n=593) and older (n=583) cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study. Males with the TT genotype displayed more ADHD-related symptoms. Adaptive impulsivity and Extraversion increased the most from age 18 to 25. While highest increases were observed in AA men, TT women exhibited the largest decreases. For participants with the AA genotype, Warmth in family was inversely associated with Neuroticism, and positively associated with Extraversion and Adaptive impulsivity. High exposure to SLE increased impulsivity and ADHD scores in TT genotype subjects. We conclude that the NPSR1 A/T polymorphism is associated with impulsivity, ADHD symptoms and personality, mirroring the activity- and anxiety-mediating role of NPSR1. Heterozygous individuals were the least sensitive to environmental factors, whereas subjects with the AA genotype and TT genotype reacted to different types of environmental adversities.

The effect of a functional NOS1 promoter polymorphism on impulsivity is moderated by platelet MAO activity

RationalePlatelet monoamine oxidase (MAO) activity is associated with impulsivity in clinical samples. Recently, a functional promoter polymorphism of neuronal nitric oxide synthase (NOS1) termed NOS1 ex1f-VNTR was found to have an effect on impulsivity-related traits and resulting psychopathology.ObjectiveThe study aims to explore the effect of both platelet MAO activity and NOS1 ex1f-VNTR genotype on impulsivity in a population-derived sample.MethodsThis study was on a non-clinical sample of adult male subjects, previously used to investigate the effect of platelet MAO activity on impulsivity-related behaviour (Paaver et al., Psychopharmacology 186:32–40, 2006). Six hundred thirty-seven male subjects were genotyped for the NOS1 ex1f-VNTR promoter polymorphism. Impulsivity was self-reported. Effects of age and smoking, known to affect platelet MAO activity, were controlled for.ResultsNo main effect of either NOS1 genotype or platelet MAO activity was present. However, significant interactions were found between effects of the NOS1 genotype and platelet MAO activity on impulsivity measures. Impulsivity and in particular the aspects of adaptive impulsivity (e.g. fast decision-making and excitement-seeking behaviour) were higher in subjects with the NOS1 ex1f-VNTR short/short genotype if they belonged to the platelet MAO medium activity (interquartile) range.ConclusionsThis study supports evidence for higher impulsivity in the NOS1 short/short genotype subjects and further suggests that this is present in the subset of subjects who have close to average platelet MAO activity.

Neuropeptide S receptor gene variant and environment: contribution to alcohol use disorders and alcohol consumption

The functional polymorphism Asn107Ile (rs324981, A > T) of the neuropeptide S receptor (NPSR1) gene is involved in the modulation of traits that affect alcohol use. Hence, we have examined whether the NPSR1 A/T polymorphism is associated with alcohol use disorders (AUD) and alcohol use in a population‐representative sample. Lifetime AUD were assessed by the MINI psychiatric interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality Behaviour and Health Study at age 25. Alcohol use, environmental adversities and personality were reported by both the younger (original n = 583) and the older cohort (original n = 593) in three study waves. NPSR1 associations with AUD and alcohol use differed by sex. In females, both AUD [odds ratio (OR) = 7.20 (0.94–55.0), P = 0.029] and harmful alcohol use were more prevalent in A‐allele carriers. In contrast, in males, AUD was more frequent in T‐allele carriers [OR = 2.75 (1.19–6.36), P = 0.017], especially if exposed to adverse environments at age 15 [OR = 10 (1.18–84.51), P = 0.019]. Alcohol use was higher in male T‐allele carriers at ages 15 and 18 as well. Similarly to females, however, the risk allele for higher alcohol use for males at age 25 was the A‐allele. Many of the effects on alcohol use were explained by genotype effects on measures of personality. In the general population, the NPSR1 Asn107Ile polymorphism is associated with AUD and alcohol consumption, dependent on sex, environment and age. The results are in line with the impulsivity and personality regulating role of the NPSR1.

Mitigating aggressiveness through education? The monoamine oxidase A genotype and mental health in general population

Objective Monoamine oxidase A (MAOA) gene promoter region includes a variable number of tandem repeat (VNTR) associated with antisocial behaviour in adverse environment. We have examined the effect of the MAOA-uVNTR on mental health and academic success by using a population representative sample and a longitudinal design. Methods The data of the older cohort (n = 593, aged 15 years at the original sampling) of the longitudinal Estonian Children Personality, Behaviour and Health Study (ECPBHS) were used. Follow-ups were conducted at ages 18 and 25 years. Aggressiveness, inattention and hyperactivity were reported by class teachers or, at older age, self-reported. Stressful life events, psychological environment in the family and interactions between family members were self-reported. Data of general mental abilities and education were obtained at the age of 25, and lifetime psychiatric disorder assessment was carried out with the Mini-International Neuropsychiatric Interview (MINI) interview. Results MAOA-uVNTR genotype had no independent effect on aggressiveness, hyperactive and inattentive symptoms, and neither was there a genotype interaction with adverse life events. Interestingly, the proportion of male subjects with higher education by the age of 25 was significantly larger among those with MAOA low-activity alleles (χ2 = 7.13; p = 0.008). Logistic regression revealed that MAOA low-activity alleles, higher mental abilities, occurrence of anxiety disorders and absence of substance-use disorder were significant independent predictors for higher education in male subjects. Conclusions In a population representative sample of young subjects, the MAOA-uVNTR ‘risk genotype’ predicted better life outcomes as expressed in higher level of education.

Further evidence for the association of the NPSR1 gene A/T polymorphism (Asn107Ile) with impulsivity and hyperactivity

Administration of neuropeptide S (NPS) elicits anxiolysis, arousal and higher activity in rodents. In humans, the NPS receptor (NPSR1) gene rs324981 A/T (Asn107Ile) polymorphism is associated with fear responses and anxiety. We have recently revealed an association of NPSR1 with impulsivity-related traits and psychopathology. In the present study the association of the NPSR1 genotype with impulsivity and attention-deficit/hyperactivity disorder (ADHD)-related symptoms was re-examined in two independent non-clinical cohorts. We used self-reports of two population-derived samples of the Estonian Psychobiological Study of Traffic Behaviour (EPSTB): a community car driving sample (n=491, MAge=37) and a driving school student sample (n=773, MAge=24). Impulsivity was measured with the Adaptive and Maladaptive Impulsivity Scale (AMIS) in both samples, and with the Barratt Impulsivity Scale (BIS) in driving schools only. For the latter sample, also measurement of ADHD symptoms was carried out with the Adult ADHD Self-Report Scale (ASRS). NPSR1 T-allele carriers had higher scores of impulsivity, motor restlessness and total ADHD scores. The effect on impulsivity originated from male participants but for ADHD symptoms the association was independent of sex. Thus we have confirmed in two additional population-derived samples that the T-allele of the NPSR1 rs324981 polymorphism is associated with increased impulsivity and ADHD-related traits.

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.

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.