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Aims: To investigate whether concurrent alcohol and tobacco use during early adolescence characterizes a subgroup that differs from users of one substance only regarding several risk factors for later substance use problems. Methods: Participants were from a prospective longitudinal cohort study of 384 children at risk for later psychopathology, with the majority being born with obstetric complications and psychosocial adversities. Assessments of adolescent drug consumption and related intrapersonal characteristics were obtained at age 15. Results: Compared to consumers of alcohol only, 15-year-olds drinking and smoking during the same time period (past 4 weeks) had significantly higher levels of consumption and more excessive use of alcohol, started drinking at an earlier age, had higher scores on the Fagerstrom Test for Nicotine Dependence, and more cannabis use. This group could be distinguished from users of alcohol only by higher novelty seeking and more positive alcohol effect expectancies. Compared to consumers of tobacco only, concurrent users reported higher nicotine dependence and more cannabis use. No significant differences were observed regarding frequency and age at initiation of tobacco use, tobacco-related sensitivity, self- efficacy and instrumentality as well as novelty seeking. Conclusions: Concurrent alcohol and tobacco use during early adolescence is associated with characteristics that are well known as risk factors for later alcohol use problems and dependence and that should be targeted by prevention programs.
Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use
(2007)
Background: Recent animal research suggests that alterations in the corticotropin releasing hormone receptor 1 (CRHR1) may lead to heavy alcohol use following repeated stress. The aim of this study was to examine interactions between two haplotype-tagging single nucleotide polymorphisms (SNPs) covering the CRHR1 gene and adverse life events on heavy drinking in adolescents. Methods: Data were available from the Mannheim Study of Children at Risk, an ongoing cohort study of the long-term outcome of early risk factors followed since birth. At age 15 years, 280 participants (135 males, 145 females) completed a self-report questionnaire measuring alcohol use and were genotyped for two SNPs (rs242938, rs1876831) of CRHR1. Assessment of negative life events over the past three years was obtained by a standardized interview with the parents. Results: Adolescents homozygous for the C allele of rs1876831 drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking in relation to negative life events than individuals carrying the T allele. No gene X environment interactions were found for regular drinking and between rs242938 and stressful life events. Conclusions: These findings provide first evidence in humans that the CRHR1 gene interacts with exposure to stressful life events to predict heavy alcohol use in adolescents.
Previous research examining gene-environment interaction (G x E) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate G x F between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort Study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This G x E replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for G x E was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.
Background: Evidence from animal studies supports a role for serotonin transporter gene promoter polymorphism (5-HTTLPR) gene-environment interaction (G X E) in the development of excessive alcohol intake. Few studies in humans have been conducted on this topic, yielding inconsistent results. The present study aims to further explore G x E between 5-HTTLPR and exposure to psychosocial adversity on alcohol consumption in a high-risk community sample of young adults. Methods: Data were collected as part of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study following the outcome of early risk factors from birth into young adulthood. At age 19 years, 309 participants (142 male participants, 167 female participants) were genotyped for the biallelic and triallelic 5-HTTLPR and were administered a 45-day alcohol timeline follow-back interview, providing measures of the total number of drinks and the number of binge drinking days. Psychosocial adversity was assessed at birth (family adversity) and at age 19 (negative life events). Results: In contrast to various previous reports, a significant G x E emerged, indicating that, when exposed to high psychosocial adversity, individuals with the LL genotype of 5-HTTLPR exhibited more hazardous drinking than those carrying the S allele or those without exposure to adversity. This effect, which was confined to male participants, held both for different classifications of 5-HTTLPR and different types of adversity. Conclusions: One explanation for the discrepant results might be heterogeneity in alcohol phenotypes. While the L allele relates more strongly to early-onset alcoholism, the S allele may be linked more closely to alcohol use associated with anxiety and depression.
Recent evidence suggests that heterogeneity in the age at onset could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with alcohol and nicotine consumption. The aim of this study was to examine interactions between two DAT1 polymorphisms and different initiation ages with regard to alcohol and tobacco consumption levels and dependence. Two hundred and ninety-one young adults (135 males, 156 females) participating in the Mannheim Study of Children at Risk were genotyped for the 40-bp variable number of tandem repeats (VNTR) and rs27072 polymorphisms of DAT1. Age at initiation was assessed at age 15 and 19 years. Information about current alcohol and tobacco consumption was obtained at age 19 years using self-report measures and structured interviews. Results suggest that age at onset of intensive consumption moderated the association of the DAT1 gene with early adult substance use and dependence, revealing a DAT1 effect only among individuals homozygous for the 10r allele of the 40-bp VNTR who had started daily smoking or being intoxicated early in life. Equally, carriers of the T allele of the rs27072 polymorphism reporting an early age at first intoxication showed higher current alcohol consumption at age 19 years. In contrast, no interaction between rs27072 and the age at first cigarette with regard to later smoking was observed. These findings provide evidence that the DAT1 gene interacts with an early heavy or regular drug exposure of the maturing adolescent brain to predict substance (ab)use in young adulthood. Further studies are required to confirm these findings.
There is ample evidence that the early initiation of alcohol use is a risk factor for the development of later alcohol-related problems. The purpose of the current study was to examine whether this association can be explained by indicators of a common underlying susceptibility or whether age at drinking onset may be considered as an independent predictor of later drinking behavior, suggesting a potential causal relationship. Participants were drawn from a prospective cohort study of the long-term outcomes of early risk factors followed up from birth onwards. Structured interviews were administered to 304 participants to assess age at first drink and current drinking behavior. Data on risk factors, including early family adversity, parental alcohol use, childhood psychopathology and stressful life events, were repeatedly collected during childhood using standardized parent interviews. In addition, information on genotype was considered. Results confirmed previous work demonstrating that hazardous alcohol consumption is related to early-adolescent drinking onset. A younger age of first drink was significantly predicted by 5-HTTLPR genotype and the degree of preceding externalizing symptoms, and both factors were related to increased consumption or harmful alcohol use at age 19. However, even after controlling for these potential explanatory factors, earlier age at drinking onset remained a strong predictor of heavy alcohol consumption in young adulthood. The present longitudinal study adds to the current literature indicating that the early onset - adult hazardous drinking association cannot solely be attributed to shared genetic and psychopathologic risk factors as examined in this study.
Background: Recent animal and human studies indicate that the exposure to alcohol during early adolescence increases the risk for heavy alcohol use in response to stress. The purpose of this study was to examine whether this effect may be the consequence of a higher susceptibility to develop "drinking to cope" motives among early initiators. Methods: Data from 320 participants were collected as part of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study. Structured interviews at age 15 and 19 were used to assess age at first alcohol experience and drunkenness. The young adults completed questionnaires to obtain information about the occurrence of stressful life events during the past 4 years and current drinking habits. In addition, alcohol use under conditions of negative states was assessed with the Inventory of Drinking Situations. Results: The probability of young adults' alcohol use in situations characterized by unpleasant emotions was significantly increased the earlier they had initiated the use of alcohol, even when controlling for current drinking habits and stressful life events. Similar results were obtained for the age at first drunkenness. Conclusions: The findings strengthen the hypothesis that alcohol experiences during early adolescence facilitate drinking to regulate negative affect as an adverse coping strategy which may represent the starting point of a vicious circle comprising drinking to relieve stress and increased stress as a consequence of drinking.
To examine whether the dopamine receptor D4 gene (DRD4) exon III VNTR moderates the risk of infants with regulatory disorders for developing attention-deficit/hyperactivity disorder (ADHD) later in childhood. In a prospective longitudinal study of children at risk for later psychopathology, 300 participants were assessed for regulatory problems in infancy, DRD4 genotype, and ADHD symptoms and diagnoses from childhood to adolescence. To examine a potential moderating effect on ADHD measures, linear and logistic regressions were computed. Models were fit for the main effects of the DRD4 genotype (presence or absence of the 7r allele) and regulatory problems (presence or absence), with the addition of the interaction term. All models were controlled for sex, family adversity, and obstetric risk status. In children without the DRD4-7r allele, a history of regulatory problems in infancy was unrelated to later ADHD. But in children with regulatory problems in infancy, the additional presence of the DRD4-7r allele increased the risk for ADHD in childhood. The DRD4 genotype seems to moderate the association between regulatory problems in infancy and later ADHD. A replication study is needed before further conclusions can be drawn, however.
Background:
Recent evidence from animal experiments and studies in humans suggests that early age at first drink (AFD) may lead to higher stress-induced drinking. The present study aimed to extend these findings by examining whether AFD interacted with stressful life events (SLE) and/or with daily hassles regarding the impact on drinking patterns among young adults.
Method:
In 306 participants of an epidemiological cohort study, AFD was assessed together with SLE during the past 3 years, daily hassles in the last month, and drinking behavior at age 22. As outcome variables, 2 variables were derived, reflecting different aspects of alcohol use: the amount of alcohol consumed in the last month and the drinking frequency, indicated by the number of drinking days in the last month.
Results:
Linear regression models revealed an interaction effect between the continuous measures of AFD and SLE on the amount of alcohol consumed. The earlier young adults had their first alcoholic drink and the higher the levels of SLE they were exposed to, the disproportionately more alcohol they consumed. Drinking frequency was not affected by an interaction of these variables, while daily hassles and their interaction with AFD were unrelated to drinking behavior.
Conclusions:
These findings highlight the importance of early age at drinking onset as a risk factor for later heavy drinking under high load of SLE. Prevention programs should aim to raise age at first contact with alcohol. Additionally, support in stressful life situations and the acquisition of effective coping strategies might prevent heavy drinking in those with earlier drinking onset.
Interindividual variability in the regulation of the human stress system accounts for a part of the individual's liability to stress-related diseases. These differences are influenced by environmental and genetic factors. Early childhood adversity is a well-studied environmental factor affecting an individual's stress response which has been shown to be modulated by gene environment interaction (GxE). Neuropeptide Y (NPY) plays a role in stress regulation and genetic variation in NPY may influence stress responses. In this study, we analyzed the association of a common variant in the NPY gene promoter, rs16147, with cortisol and ACTH responses to acute psychosocial stress in young adults from the Mannheim Study of Children at Risk (MARS), an ongoing epidemiological cohort study following the outcome of early adversity from birth into adulthood. We found evidence of a GxE interaction between rs16147 and early adversity significantly affecting HPA axis responses to acute psychosocial stress. These findings suggest that the neurobiological mechanisms linking early adverse experience and later neuroendocrine stress regulation are modulated by a gene variant whose functional relevance is documented by increasing convergent evidence from in vitro, animal and human studies.
Evidence from animal research has revealed that less maternal care results in disturbed emotionality in the offspring. In the present study, the long-term impact of maternal responsiveness and stimulation during early mother child interaction on depressive psychopathology was examined until adulthood. Data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness and stimulation as well as infant responsiveness were evaluated by trained raters. At age 19 years, 314 participants (145 males, 169 females) were characterized on measures of depression through interview and questionnaire. In addition, measures of depression and anxiety were available from assessments in childhood. Results indicated that less maternal stimulation during early interaction was associated with a higher risk of depression in the offspring until the age of 19 years. In addition, children of less stimulating mothers showed more depressive symptoms at age 19 years and displayed more anxiety and depressive symptoms between the ages of 4.5 and 15 years. In contrast, maternal responsiveness was unrelated to children's outcome. In accordance with findings from animal research, the present study provides first longitudinal evidence in humans of a continuous and long-term influence of early maternal interaction behavior on the offspring's psychological adjustment until adulthood. The results suggest that the amount of maternally initiated contact behavior in a very early developmental stage may be crucial for children's mental health, regardless of child and maternal responsiveness.
Background: Recently, first evidence has been reported for a geneparenting interaction (G x E) with regard to adolescent alcohol use. The present investigation set out to extend this research using the catechol-O-methyltransferase (COMT) Val158Met polymorphism as a genetic susceptibility factor. Moreover, the current study examined whether a potential G x E would be consistent with one of two models of geneenvironment interplay (genetic vulnerability vs. differential susceptibility). Methods: Data were collected as part of an ongoing epidemiological cohort study following the outcome of early risk factors from birth into adulthood. Two hundred and eighty-five participants (130 males, 155 females) were genotyped for the COMT Val(158) Met polymorphism and were administered an alcohol interview, providing measures of current frequency and amount of drinking at ages 15 and 19 years. Information on three dimensions of perceived parenting behavior was obtained from the 15-year-olds. Results: Adolescents homozygous for the Met allele showed higher drinking activity at age 19 years when their parents had engaged in less supervision or were less involved, while their drinking activity was reduced under conditions of favorable parenting. No such relationship was found in individuals carrying the Val allele. Conclusions: The present findings correspond with the pattern of results predicted by the differential susceptibility hypothesis, suggesting that environmental variation would have a greater impact in individuals carrying a genetic susceptibility such that, in this group, exposure to negative environmental conditions would result in more adverse outcomes and the experience of favorable conditions would lead to more positive outcomes.
BackgroundEarly alcohol use is one of the strongest predictors of later alcohol use disorders, with early use usually taking place during puberty. Many researchers have suggested drinking during puberty as a potential biological basis of the age at first drink (AFD) effect. However, the influence of the pubertal phase at alcohol use initiation on subsequent drinking in later life has not been examined so far.
MethodsPubertal stage at first drink (PSFD) was determined in N=283 young adults (131 males, 152 females) from an epidemiological cohort study. At ages 19, 22, and 23years, drinking behavior (number of drinking days, amount of alcohol consumed, hazardous drinking) was assessed using interview and questionnaire methods. Additionally, an animal study examined the effects of pubertal or adult ethanol (EtOH) exposure on voluntary EtOH consumption in later life in 20 male Wistar rats.
ResultsPSFD predicted drinking behavior in humans in early adulthood, indicating that individuals who had their first drink during puberty displayed elevated drinking levels compared to those with postpubertal drinking onset. These findings were corroborated by the animal study, in which rats that received free access to alcohol during the pubertal period were found to consume more alcohol as adults, compared to the control animals that first came into contact with alcohol during adulthood.
ConclusionsThe results point to a significant role of stage of pubertal development at first contact with alcohol for the development of later drinking habits. Possible biological mechanisms and implications for prevention are discussed.
There is converging evidence suggesting a particular susceptibility to the addictive properties of nicotine among adolescents. The aim of the current study was to prospectively ascertain the relationship between age at first cigarette and initial smoking experiences, and to examine the combined effects of these characteristics of adolescent smoking behavior on adult smoking. It was hypothesized that the association between earlier age at first cigarette and later development of nicotine dependence may, at least in part, be attributable to differences in experiencing pleasurable early smoking sensations. Data were drawn from the participants of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study from birth to adulthood. Structured interviews at age 15, 19 and 22 years were conducted to assess the age at first cigarette, early smoking experiences and current smoking behavior in 213 young adults. In addition, the participants completed the Fagerstrom Test for Nicotine Dependence. Adolescents who smoked their first cigarette at an earlier age reported more pleasurable sensations from the cigarette, and they were more likely to be regular smokers at age 22. The age at first cigarette also predicted the number of cigarettes smoked and dependence at age 22. Thus, both the age of first cigarette and the pleasure experienced from the cigarette independently predicted aspects of smoking at age 22.
Maternal stimulation in infancy predicts hypothalamic-pituitary-adrenal axis reactivity in young men
(2013)
Evidence from animal research has demonstrated the effect of early maternal care on the offspring's endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother-child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19 years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3 months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic-pituitary-adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring's hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.
Accumulating research suggests a moderating role for the corticotropin-releasing hormone receptor 1 gene (CRHR1) in the association between childhood adversity and adult depression. The present study aims to replicate recent findings using different genetic variants and measures of early adversity assessed both prospectively and retrospectively. Data were collected in the context of an ongoing epidemiological cohort study following the outcome of early risk factors from birth into adulthood. 300 participants (137 males, 163 females) were genotyped for four CRHR1 SNPs (rs7209436, rs110402, rs242924, and rs17689882) and completed the Beck Depression Inventory at ages 19, 22 and 23 years. Childhood adversity was assessed using the Childhood Trauma Questionnaire and by a standardized parent interview yielding an index of family adversity. Our results indicate that CRHR1 and childhood adversity interacted to predict depressive symptoms in young adults. Specifically, we found that the impact of childhood maltreatment on adult depressive symptoms was significantly higher in individuals (i) with two copies of the CRHR1 TAT haplotype, and (ii) homozygous for the G allele of rs17689882. The interaction was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report, but not to prospectively ascertain objective family adversity. The present study partially replicates recent findings of a CRHR1 by childhood adversity interaction with regard to adult depression highlighting the subjective characteristics of the environmental pathogen that is operative in this interaction.
Background: Clock genes govern circadian rhythms and shape the effect of alcohol use on the physiological system. Exposure to severe negative life events is related to both heavy drinking and disturbed circadian rhythmicity. The aim of this study was 1) to extend previous findings suggesting an association of a haplotype tagging single nucleotide polymorphism of PER2 gene with drinking patterns, and 2) to examine a possible role for an interaction of this gene with life stress in hazardous drinking.
Methods: Data were collected as part of an epidemiological cohort study on the outcome of early risk factors followed since birth. At age 19 years, 268 young adults (126 males, 142 females) were genotyped for PER2 rs56013859 and were administered a 45-day alcohol timeline follow-back interview and the Alcohol Use Disorders Identification Test (AUDIT). Life stress was assessed as the number of severe negative life events during the past four years reported in a questionnaire and validated by interview.
Results: Individuals with the minor G allele of rs56013859 were found to be less engaged in alcohol use, drinking at only 72% of the days compared to homozygotes for the major A allele. Moreover, among regular drinkers, a gene x environment interaction emerged (p = .020). While no effects of genotype appeared under conditions of low stress, carriers of the G allele exhibited less hazardous drinking than those homozygous for the A allele when exposed to high stress.
Conclusions: These findings may suggest a role of the circadian rhythm gene PER2 in both the drinking patterns of young adults and in moderating the impact of severe life stress on hazardous drinking in experienced alcohol users. However, in light of the likely burden of multiple tests, the nature of the measures used and the nominal evidence of interaction, replication is needed before drawing firm conclusions.