Genome-wide meta-analysis identifies novel loci conferring risk of acne vulgaris.

Acne vulgaris is a common chronic skin disorder presenting with comedones, cystic structures forming within the distal hair follicle, and in most cases additionally with inflammatory skin lesions on the face and upper torso. We performed a genome-wide association study and meta-analysis of data from 34,422 individuals with acne and 364,991 controls from three independent European-ancestry cohorts. We replicated 19 previously implicated genome-wide significant risk loci and identified four novel loci [11q12.2 (FADS2), 12q21.1 (LGR5), 17q25.3 (FASN), and 22q12.1 (ZNRF3-KREMEN1)], bringing the total number of reported acne risk loci to 50. Our meta-analysis results explain 9.4% of the phenotypic variance of acne. A polygenic model of acne risk variants showed that individuals in the top 5% of the risk percentiles had a 1.62-fold (95% CI 1.47-1.78) increased acne risk relative to individuals with average risk (20-80% on the polygenic risk score distribution). Our findings highlight the Wnt and MAPK pathways as key factors in the genetic predisposition to acne vulgaris, together with the effects of genetic variation on the structure and maintenance of the hair follicle and pilosebaceous unit. Two novel loci, 11q12.2 and 17q25.3, contain genes encoding key enzymes involved in lipid biosynthesis pathways.

Variation rs6971 in the Translocator Protein Gene (TSPO) is Associated with Aggressiveness and Impulsivity but Not with Anxiety in a Population-Representative Sample of Young Adults.

Expression of the 18-kDa translocator protein (TSPO), originally identified as a peripheral benzodiazepine receptor, has been found to be altered in several psychiatric disorders. A common single nucleotide polymorphism (rs6971) in the TSPO gene leads to an amino acid substitution, Ala147Thr, which dramatically alters the affinity with which TSPO binds drug ligands. As cholesterol also binds TSPO in the same transmembrane domain, it is suggested that this substitution may impair the ability of TSPO to bind or import cholesterol, and hence may affect steroid synthesis and hypothalamic-pituitary-adrenal function. The analysis was carried out on older birth cohort (n = 655) of the longitudinal Estonian Children Personality, Behavior and Health Study sample. Anxiety, aggressive behavior, impulsiveness, and history of stressful life events were self-reported in various data collection waves. Psychiatric assessment of lifetime prevalence of anxiety disorders was carried out at 25 years of age by experienced clinical psychologists. TSPO rs6971 was genotyped in all participants. TSPO rs6971 was not associated with self-reported levels of anxiety or lifetime prevalence of anxiety disorders. However, participants homozygous for the minor A allele displayed the highest aggressiveness and dysfunctional impulsivity scores. The positive, adaptive aspect of impulsivity was sensitive to stressful life events, as the AA genotype was associated with functional impulsivity only when the participants had experienced a low number of stressful life events during childhood. TSPO rs6971 polymorphism may be related to development of aggressiveness and impulsivity by adulthood, regardless of the participants' gender.

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.

Effects of HTR1A rs6295 polymorphism on emotional attentional blink.

People prone to mood disorders and anxiety typically show increased sensitivity to task­irrelevant stimulation signifying threat. Better knowledge about the brain mechanisms mediating this sensitivity as well as about individual inherited differences in how these mechanisms function is a precondition for developing improved vulnerability screening, resilience building and treatment methods. The chances to have affective disorders are known to depend, among other factors, on the functioning of the brain serotonin systems developed under influence from common genetic variability. However, the extent and directions of the effects of SNPs involved in serotonergic regulation on the propensity for suboptimal threat­sensitivity are poorly understood. This applies also to HTR1A rs6295 polymorphism. Assisted by our custom developed emotional attentional blink task, we found that nonclinical subjects carrying the G allele (compared to C allele homozygotes) had higher sensitivity to threat­depicting distractor stimuli, expressed as an increase in the blink magnitude. We also disrupted right­hemisphere dorsolateral prefrontal cortex by rTMS (repetitive transcranial magnetic stimulation) to look for the possible role of DLPFC (dorsolateral prefrontal cortex; known to be involved in cognitive control of responses to affective stimuli) in serotonergic regulation mediated by the HTR1A rs6295 polymorphism. No main effects or interactions with rTMS being involved were found.

Associations of attention distractibility with attention deficit and with variation in the KTN1 gene.

Attention distractibility in a low load visual search experiment with a rare irrelevant distractor could be an objective continuous measure in adulthood that correlates well with the symptoms of attention deficit throughout lifespan. This was studied using a birth cohort representative sample in a longitudinal study. The expected correlations were not found between the distractor cost measured in the experiment in adulthood and the inattention questionnaire scores from ages 15-33. However, the coefficient of variability for RT (CVRT) correlated negatively with self-reported motor restlessness (age 15) and attention deficit (age 25). We suggest that hyperactivity in childhood improved motor control at age 33. Associations with the gene KTN1 rs945270 (found to affect putamen size) were explored. CVRT, motor restlessness at age 15 and attention deficit scores at age 25 were especially low for male C-allele carriers. A possible association with the volume of putamen of individual participants is considered.

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.

Nitric oxide synthase genotype interacts with stressful life events to increase aggression in male subjects in a population-representative sample.

Nitric oxide signalling has been implicated in impulsive and aggressive traits and behaviours in both animals and humans. In the present study, we investigated the effects of a functional variable number of tandem repeats (VNTR) polymorphism in exon 1f (ex1f) of the nitric oxide synthase 1 (NOS1) gene (NOS1 ex1f-VNTR) and stressful life events on aggressive behaviour in population representative sample of adolescents followed up from third grade to 25 years of age. We studied the younger cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study (subjects in the last study wave n = 437, males n = 193; mean age 24.8 ± 0.5 years). Aggressive behaviour was rated at age 25 with the Illinois Bully Scale and Buss-Perry Aggression Questionnaire. Life history of aggression was evaluated in a structured interview. Stressful life events and family relationships were self-reported at age 15. The hypothesized risk genotype (homozygosity for the short allele) was associated with higher levels of aggression in males (statistical significance withstanding the multiple correction procedure). Exposure to stressful life events or adverse family relationships was associated with increased aggressive behaviour in subjects homozygous for either of the alleles, and these associations were mostly observed in males. However, these associations in these stratified analyses did not survive correction for multiple testing. Aggressiveness was relatively unaffected by the NOS1 ex1f-VNTR genotype in the female subjects even when taking exposure to childhood adversity into account. Our findings support the hypothesized involvement of a functional NOS1 polymorphism on aggression in a population representative sample of young adults.

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.

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.

BDNF polymorphism in non-veridical decision making and differential effects of rTMS.

Making decisions when an objectively correct option is not obvious, involves different neurobiological mechanisms than "veridical" decision making. The dorsolateral prefrontal cortex (DLPFC) exhibits a distinct pattern of prefrontal activation in non-veridical cognition, but little is known about the role of underlying neurobiological endophenotypes. A functional polymorphism in the brain-derived neurotrophic factor (BDNF) gene, causing a valine (Val) to methionine (Met) amino acid substitution at codon 66, has been shown to be associated with structural and functional changes in DLPFC and affect veridical decision making. We hypothesized that the BDNF genotype may be related to non-veridical cognition. We explored whether the BDNF Val66Met polymorphism affected preferences in a cognitive task devoid of intrinsically correct or false choice, using the Cognitive Bias Task (CBT). We also studied if manipulating the right DLPFC with rTMS stimulation changes non-veridical preferences. Sixteen healthy adults, including 9 Val/Val and 7 Val/Met subjects, participated in the study. Participants with Val/Met genotype expressed a more context-independent, internally driven choice selection preference. Val/Val subjects' selection was more dependent on the context, driven by the properties of external stimuli. rTMS stimulation enhanced a preexisting bias in choice preferences. In Val/Val subjects, TMS stimulation shifted the non-veridical preference bias towards greater dependence on external context, while in Val/Met subjects the CBT score became more context-independent. Our study showed that BDNF genotype is associated with a bias in non-veridical preferences and that Val/Val and Val/Met subjects respond differently to right DLPFC rTMS stimulation, further enhancing their preexisting selection biases.

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'.

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

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.

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.

Risky driving and the persistent effect of a randomized intervention focusing on impulsivity: The role of the serotonin transporter promoter polymorphism.

Road traffic accidents are a serious public health issue, and real-life traffic offences are an excellent indicator of the behavioural tendencies of impulsivity and risk-taking. We have previously reported on short-term efficacy of a brief intervention in driving schools to reduce traffic risks (Paaver et al., Accid. Anal. Prev., 2013; 50, 430-437), and have now addressed the question of whether does the impact of the intervention last for a few years, and whether traffic behaviour and the intervention effect are associated with the serotonin transporter polymorphism (5-HTTLPR) genotype as the central serotonin system is strongly associated with impulse control. Participants of the study were 1866 novice car-drivers (mean age 23.0, SD = 7.2 years). Data on traffic violations were obtained four years after intervention from the police database and on traffic collisions from the national traffic insurance database. DNA samples were available for 767 participants and 5-HTTLPR genotypes were classified using the triallelic model. For the observation period after the intervention, speeding, drunk driving and involvement in traffic accidents were significantly lower in the intervention group. 5-HTTLPR genotype was associated with traffic behaviour: The S'-allele carriers had significantly lower odds for speeding offences and traffic accidents. The lower prevalence of S'-allele carriers among those who had committed speeding offences was statistically significant in females, while the lower prevalence of having been involved in a traffic accident was rather observed in males. Statistically significant intervention effects were observed only in the L'/L' homozygotes who had higher prevalence of traffic incidents. Conclusively, the brief intervention in traffic schools had a significant impact on traffic safety within subsequent four years, and traffic behaviour was associated with the serotonin transporter genotype. These findings suggest that subjects who are less likely to self-regulate their driving habits while gaining experience would benefit from training of impulsivity recognition.

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.

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.

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.

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.