Geenid ja alkoholitarvitamine: levinud geenipolümorfismide mõju rahvastikus

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Alkoholi kuritarvitamine on üks peamistest ennetatavate surmade ja terviserikete põhjustajatest. Lähtuvalt sellest, kui palju probleeme tekib tarvitajale endale ja teda ümbritsevatele, on alkohol loetud kõige kahjulikumaks uimastiks1. Kuigi olukord on tasapisi paranemas, paistab Eesti rahvusvahelisel tasandil veel jätkuvalt silma ohtra alkoholitarbimisega2. Mehed tarvitavad alkoholi ning kogevad alkoholiga seotud probleeme enamasti rohkem kui naised. Nii ka meie rahvastikupõhises pikaajalises sünnikohortide uuringus – poisid alustasid alkoholi tarvitamisega varem ning tegelesid sellega sagedamini kui tüdrukud. Nooreks täiskasvanueaks oli selle tulemusena meeste seas tunduvalt rohkem neid, kes alkoholi kuritarvitamisega hädas. Alkoholiprobleemide kogemise tõenäosust tõstsid ka stressirikkad elusündmused ning halvad suhted pereliikmete ja õpetajatega. Kuna alkoholism on krooniline ja ravile raskesti alluv, on selle haiguse tekkimist ennustavate bioloogiliste näitajate uurimine äärmiselt päevakajaline. Analüüsides geenide mõju alkoholitarbimisele, leidsime, et probleemset alkoholitarbimist ennustasid just sellised geneetilised eripärad, mis olid seotud madalama stressitaluvuse ja suurema avatusega keskkondlike mõjude suhtes. Seosed ei olnud aga üleüldised ja sõltusid suures osas sünnikohordist – perioodist, mil inimene sündinud oli. Sotsiaalsed normid ja hoiakud alkoholi tarbimisse koonduvad sünnikohortide kaupa ning mõjutavad otseselt uimastite tarvitamist. 1990. aastatel alguse saanud kiired ühiskondlikud muutused mõjutavad meie siirdeühiskonnas väärtushinnanguid, vaba aja tegevusi, suhteid ja igapäevast toimetulekut. Kultuurilised ja ühiskondlikud muutused vormivad pidevalt inimeste identiteeti ja elustiili ning võivad vahendada ka geeniefekte alkoholitarbimisele. [1 Nutt DJ, King LA, Phillips LD (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet 376:1558-1565. 2 OECD (2015) Tackling harmful alcohol use: Economics and public health policy. OECD Publishing.]Problematic use of alcohol is one of the leading causes of preventable deaths and disability. Based on the harm to the user and others, alcohol has been considered to be the most harmful drug1. Men generally drink more alcohol and have more alcohol-related problems than women. Also in our population-representative longitudinal birth cohort study in Estonia, the boys started consuming alcohol earlier and were more frequent alcohol consumers than girls. By young adulthood, there were significantly more men than women diagnosed with alcohol use disorder. The more frequent was the alcohol consumption during the teenage years, the more problable was the occurrence of alcohol problems by young adulthood. In addition, the more stressful life events, the worse relationships with family members and with teachers the children experienced, the higher was the likelihood of developing alcohol use problems later on in life. The chronic nature of alcoholism is the reason why the search for predictive biomarkers is so urgent. When we analyzed the effects of common genetic variances on alcohol use and abuse, the genotypes associated with higher levels of stress reactivity and openness to environmental influences were the ones also linked to problematic alcohol use. However, the relations were not universal and strongly depended on birth cohort – the time period when one was born. Social norms and attitudes regarding alcohol use cluster in birth cohorts, and this clustering has a direct effect on drug use. The rapid socioeconomic changes that have taken place in Estonia since the beginning of 1990s and are still ongoing affect the values, activities, relationships, leisure time choices and everyday functioning of the people living in this transition society. Cultural transformation processes continuously shape the identities and lifestyles of individuals, and can also moderate the genetic effects on alcohol consumption. [1 Nutt DJ, King LA, Phillips LD (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet 376:1558-1565.

Efficacy of intervention at traffic schools reducing impulsive action, and association with candidate gene variants

OBJECTIVE: Road traffic injuries are the leading cause of death among young people. Recognition of the contribution of impulsive behaviour may help novice drivers to behave more safely. Previously a brief intervention focusing on impulsive traffic behaviour conducted by psychologists in driving schools had been effective. The aim of this study was an independent re-evaluation of the effect of the intervention, as conducted by driving school teachers, and assessment of the potential associations with candidate genotypes. METHODS: Driving school students (mean age 22.5, SD=7.9) were divided into intervention (n=704) and control (n=737) groups. Driving school teachers were trained to administer the intervention which consisted of a lecture and group work (1.5 h in total) on impulsivity. Traffic offences and crashes were monitored during 3 years, using police and traffic insurance fund databases. Functional polymorphisms of the dopamine transporter (DAT) and serotonin transporter genes (DAT1 VNTR and 5-HTTLPR) were assessed. RESULTS: The intervention significantly lowered general traffic risk and prevalence of traffic accidents. DAT1 VNTR 9R carriers, particularly males, had higher general traffic risk in the whole sample. Female 5-HTTLPR s' allele carriers of the intervention group had the lowest general traffic risk. Intervention was most effective in female DAT1 VNTR 10R/10R homozygotes. CONCLUSIONS: Brief impulsivity-centred intervention appears as a promising strategy for preventing risk-taking behaviour in novice drivers and can be fully integrated to driving school curriculum

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

Relapse of drunk driving and association with traffic accidents, alcohol-related problems, and biomarkers of impulsivity

Objective: Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. Methods: We have longitudinally examined the behaviour of drunk drivers (n=203) and controls (n=211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. Results: The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. Conclusions: Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities

Association of the COMT Val108/158Met genotype with professional career and education: The Val-allele is more frequent in managers and in enterprising occupations

Catechol-O-methyl transferase (COMT) is a key player in neurotransmission by catecholamines, and the functional COMT Val108/158Met polymorphism is strongly related to prefrontal reactivity and to dopamine levels. As dopamine is a critically important neurotransmitter in cognition, emotion and motivation, we addressed the potential impact of this genotype on life course by examining its association with being in enterprising professions. The parents (n = 1410) of the target subjects in the Estonian Children Personality Behaviour and Health Study reported their current occupation, and those classified as enterprising (n = 197; 18%) were compared with the remaining group. Additionally, the subjects self-classified themselves according to the International Standard Classification of Occupations and the group of managers (6.2%) was compared to other groups. We found that the COMT Val108/158Met Val/Val homozygotes were overrepresented among enterprising occupations and the Val-allele carriers among self-classified managers. While several measures associated with the Val/Val homozygosity were also associated with enterprising occupation, no simple path from the genotype to enterprising occupations emerged from structural equation models, suggesting that the COMT Val108/158Met genotype contributes to choices of profession via multiple interactive features. We also reproduced a previous finding that the COMT genotype is associated with educational attainment in a gender-dependent manner

Association of FTO rs1421085 with obesity, diet, physical activity and socioeconomic status: a longitudinal birth cohort study

Background and aims Fat mass and obesity-associated protein (FTO) variants are among genetic variants frequently associated with obesity. We analyzed the association between FTO rs1421085 polymorphism and obesity, dietary intake, cardiorespiratory fitness (CRF), physical activity, and socioeconomic status (SES) from the age of 9–25 years. Methods and results The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between FTO rs1421085 and obesity, dietary intake, CRF, physical activity, and SES from the age of 15–25 years was assessed using linear mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, and 25 years were assessed by one-way ANOVA. Male C-allele carriers had significantly (p < 0.05) higher body mass index (BMI), sum of 5 skinfolds, body fat percentage, and hip circumference from the age of 15–25 years. Findings were similar at the age of 9 years. In female subjects, waist-to-hip ratio was significantly greater in CC homozygotes. Interestingly, female CC homozygotes had a greater decrease in the rate of change in daily energy intake and lipid intake per year and higher physical activity score at every fixed time point. Moreover, in females, an effect of FTO × SES interaction on measures of obesity was observed. Conclusion The FTO rs1421085 polymorphism was associated with obesity and abdominal obesity from childhood to young adulthood in males, and with abdominal obesity from adolescence to young adulthood in females. This association is rather related to differences in adipocyte energy metabolism than lifestyle

Orexin/hypocretin receptor gene (HCRTR1) variation is associated with aggressive behaviour

Orexins, alternatively called hypocretins, are neuropeptides with crucial role in maintaining wakefulness. The orexin system is thought to mediate a coordinated defense response but thus far investigated from the flight, but never fight, response perspective. An HCRTR1 gene variant (rs2271933 G > A) leading to amino acid substitution (Ile408Val) has been associated with migraine and mood disorders. We genotyped, and assessed aggressive behaviour in both birth cohorts (n = 655 and 583) of the Estonian Children Personality Behaviour and Health Study (ECPBHS). Measures of aggressiveness were collected at age 25 or 33 and data on stressful life events (SLE-s) at age 15. Violations of traffic law were monitored in the samples of the Estonian Psychobiological Study of Traffic Behaviour. In both birth cohorts of the ECPBHS, the HCRTR1 the A/A homozygotes reported higher aggression in both Buss-Perry Aggression Questionnaire and the Life History of Aggression Interview. With either measure of aggressiveness, the HCRTR1 genotype effect was dependent on experience of SLE, the highest level of aggressiveness increase by environment being found in female A/A homozygotes. The HCRTR1 A/A homozygotes scored higher in the ANGER facet of the Affective Neuroscience Personality Scale, while such an effect on FEAR was found only in females. Male HCRTR1 A/A homozygotes were more likely to relapse into drunk driving of a passenger car, and in two independent samples the A-allele carriers were causing traffic accidents more often. Conclusively, self-report, interview, and traffic record data converge indicating that the HCRTR1 Ile408Val genotype is associated with aggressiveness and breach of law. This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’

Variants of the aggression-related RBFOX1 gene in a population representative birth cohort study: aggressiveness, personality and alcohol use disorder

Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples. Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss-Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied. Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder. Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness

RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior

The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype