Prenatal cannabis exposure is associated with alterations in offspring DNA methylation at genes involved in neurodevelopment, across the life course.

Prenatal cannabis exposure (PCE) is of increasing concern globally, due to the potential impact on offspring neurodevelopment, and its association with childhood and adolescent brain development and cognitive function. However, there is currently a lack of research addressing the molecular impact of PCE, that may help to clarify the association between PCE and neurodevelopment. To address this knowledge gap, here we present epigenome-wide association study data across multiple time points, examining the effect of PCE and co-exposure with tobacco using two longitudinal studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Christchurch Health and Development Study (CHDS) at birth (0 y), 7 y and 15-17 y (ALSPAC), and ~27 y (CHDS). Our findings reveal genome-wide significant DNA methylation differences in offspring at 0 y, 7 y, 15-17 y, and 27 y associated with PCE alone, and co-exposure with tobacco. Importantly, we identified significantly differentially methylated CpG sites within the genes LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, and LRP5 that are shared between different time points throughout development in offspring. Notably, functional pathway analysis showed enrichment for differential DNA methylation in neurodevelopment, neurotransmission, and neuronal structure pathways, and this was consistent across all timepoints in both cohorts. Given the increasing volume of epidemiological evidence that suggests a link between PCE and adverse neurodevelopmental outcomes in exposed offspring, this work highlights the need for further investigation into PCE, particularly in larger cohorts.

DNA methylation analysis using bisulphite-based amplicon sequencing of individuals exposed to maternal tobacco use during pregnancy, and offspring conduct problems in childhood and adolescence.

Maternal tobacco smoking during pregnancy is a large driver of health inequalities and a higher prevalence of conduct problem (CP) has been observed in exposed offspring. Further, maternal tobacco use during pregnancy can also alter offspring DNA methylation. However, currently, limited molecular evidence has been found to support this observation. Thus we aim to examine the association between maternal tobacco use in pregnancy and offspring CP, to determine whether offspring CP is mediated by tobacco exposure-induced DNA methylation differences. Understanding the etiology of the association between maternal tobacco use and offspring CP will be crucial in the early identification and treatment of CP in children and adolescents. Here, a sub group of N =96 individuals was sourced from the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years in New Zealand. Whole blood samples underwent bisulphite-based amplicon sequencing at 10 loci known to play a role in neurodevelopment, or which had associations with CP phenotypes. We identified significant (P CYP1A1 , ASH2L and MEF2C in individuals with CP who were exposed to tobacco in utero . We conclude that environmentally-induced DNA methylation differences could play a role in the observed link between maternal tobacco use during pregnancy and childhood/adolescent CP. However, larger sample sizes are needed to produce an adequate amount of power to investigate this interaction further.

Attitudes towards cannabis and cannabis law change in a New Zealand birth cohort.

AIMS: Personal cannabis use is common across New Zealand, and an upcoming referendum will enable the public to vote on whether this should be legalised. The present research aimed to examine the attitudes of midlife New Zealand adults on cannabis use and legalisation, and to identify potential predictors of those attitudes. METHODS: At age 40, 899 participants drawn from the Christchurch Health and Development Study were interviewed about the perceived harmfulness of cannabis use, opinions on legalisation for recreational use and supply, and the use of cannabis for medicinal purposes. In addition, a range of potential predictors of legislative attitudes were examined. RESULTS: We identified a wide range of attitudes across the cohort, however the majority tended to hold a neutral view. More than 80% of the cohort expressed support for medicinal cannabis, while 47.8% supported decriminalisation, and 26.8% expressed support for legalisation for recreational use. The strongest predictors of support for legalisation were prior use of cannabis and other drugs, while additional positive predictors included a history of depression, Maori ancestry, parental drug use, novelty seeking and higher educational attainment. Predictors of more negative attitudes were also identified, and included female gender and having dependent children. CONCLUSIONS: These findings provide insight into cannabis-related views within the New Zealand context, and may help to predict voting behaviour during the 2020 Cannabis Referendum.

Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort.

Cannabis use is of increasing public health interest globally. Here we examined the effect of heavy cannabis use, with and without tobacco, on genome-wide DNA methylation in a longitudinal birth cohort (Christchurch Health and Development Study, CHDS). A total of 48 heavy cannabis users were selected from the CHDS cohort, on the basis of their adult exposure to cannabis and tobacco, and DNA methylation assessed from whole blood samples, collected at approximately age 28. Methylation in heavy cannabis users was assessed, relative to non-users (n = 48 controls) via the Illumina Infinium® MethylationEPIC BeadChip. We found the most differentially methylated sites in cannabis with tobacco users were in the AHRR and F2RL3 genes, replicating previous studies on the effects of tobacco. Cannabis-only users had no evidence of differential methylation in these genes, or at any other loci at the epigenome-wide significance level (P < 10-7). However, there were 521 sites differentially methylated at P < 0.001 which were enriched for genes involved in neuronal signalling (glutamatergic synapse and long-term potentiation) and cardiomyopathy. Further, the most differentially methylated loci were associated with genes with reported roles in brain function (e.g. TMEM190, MUC3L, CDC20 and SP9). We conclude that the effects of cannabis use on the mature human blood methylome differ from, and are less pronounced than, the effects of tobacco use, and that larger sample sizes are required to investigate this further.

Social Causation, Social Selection, or Common Determinants? Examining Competing Explanations for the Link Between Young Adult Unemployment and Nicotine Dependence.

INTRODUCTION: Unemployment has been related to smoking, yet the causal nature of the association is subject to continued debate. Social causation argues that unemployment triggers changes in smoking, whereas the social selection hypothesis proposes that pre-existing smoking behavior lowers the probability of maintaining employment. The present study tested these competing explanations while accounting for another alternative explanation-common liability. METHODS: Data were from the Christchurch Health and Development Study, a longitudinal cohort followed from birth to age 35. Odds were generated for having nicotine dependence in models for social causation and being unemployed in models for social selection. These models were extended to include possible common liability factors during childhood (eg, novelty seeking) and young adulthood (eg, major depression). RESULTS: In the model testing social causation, coefficients representing the impacts of unemployment on nicotine dependence remained statistically significant and robust (odds ratio [OR] = 1.55; 95% confidence interval [CI] = 1.20, 2.00), even after accounting for common determinant measures. In contrast, a reverse social selection model revealed that coefficients representing the impacts of nicotine dependence on unemployment substantially attenuated and became statistically nonsignificant as childhood factors were added (OR = 1.14; 95% CI = 0.90, 1.45). CONCLUSIONS: Unemployment may serve as inroads to nicotine addiction among young adults, not the other way, even in the context of nicotine dependence, a more impaired form of smoking that may arguably hold higher potential to generate social selection processes. This social causation process cannot be completely attributable to common determinant factors. IMPLICATIONS: It is critical to clarify whether unemployment triggers changes in smoking behaviors (ie, social causation) or vice versa (ie, social selection)-the answers to the question will lead to public health strategies with very different intervention targets to break the linkage. The current study findings favor social causation over social selection, regardless of gender, and support a needed shift in service profiles for unemployed young adults-from a narrow focus on job skills training to a more holistic approach that incorporates knowledge from addiction science in which unemployed young adults can find needed services to cope with job loss.

Comparison of age of first drink and age of first intoxication as predictors of substance use and mental health problems in adulthood.

BACKGROUND: International public policy on age of first alcoholic drink (AFD) has emphasised the long-term benefits of delaying AFD. This study aimed to compare AFD to age of first intoxication (AFI) as predictors of substance use disorder and mental disorder outcomes in adulthood. METHODS: Data were obtained from a longitudinal birth cohort in Christchurch, New Zealand. Participants were born in 1977. Analysis samples ranged from n = 1025 (age 18) to n = 962 (age 35). Measures of AFD and AFI were generated using parental- and self-report data collected from age 11. Outcomes at age 18-35 were alcohol quantity consumed, DSM-IV alcohol use disorder (AUD) and AUD symptoms, major depression, anxiety disorder, and nicotine, cannabis, and other illicit drug dependence. Covariate factors measured during childhood included family socioeconomic status, family functioning, parental alcohol-related attitudes/behaviours, and individual factors. RESULTS: There was a significant unadjusted association between AFD and symptoms of AUD (p < .001) and nicotine dependence (p < .05) but not other outcomes. AFI was significantly (p < .05) associated with all outcomes. After adjustment for covariates, the association between AFD and outcomes was not statistically significant. Conversely, in adjusted models, statistically significant (p < .05) associations remained between AFI and all AUD and substance use disorder outcomes but not alcohol consumption or mental disorder outcomes. CONCLUSIONS: AFI was a more robust predictor of adult substance use disorder outcomes than AFD. Public health and policy interventions aimed at prevention of long term harms from alcohol should therefore focus on AFI rather than AFD.

Unemployment and substance use problems among young adults: Does childhood low socioeconomic status exacerbate the effect?

The current study tested whether unemployment predicted young adults' heavy episodic drinking, cigarette smoking, and cannabis use after taking into account individual development in substance use. Furthermore, building on the life course perspective, this study examined whether the link between unemployment and substance use among young adults differed for those who experienced low childhood SES compared to those who did not. Data for the present study came from the Seattle Social Development Project (SSDP), a panel study examining a broad range of developmental outcomes from ages 10 to 33. A life history calendar (LHC) was administered to assess substance use and unemployment status during young adulthood. Covariates included baseline symptoms of psychopathology, baseline substance use, gender, ethnicity, and adult educational attainment. Results suggest that unemployment is associated with young adults' heavy episodic drinking and possibly cigarette use, but not cannabis use. Moreover, for all three substances, the detrimental impact of unemployment on substance use seems to be exacerbated among young adults who spent their childhood and adolescence in a lower SES household. Public health efforts that provide other viable and affordable options to cope with unemployment among young adults from low SES backgrounds are needed to address this disproportionate concentration of adverse impacts of unemployment on behavioral health.

Psychosocial sequelae of cannabis use and implications for policy: findings from the Christchurch Health and Development Study.

BACKGROUND: The Christchurch Health and Development Study is a longitudinal study of a birth cohort of 1265 children who were born in Christchurch, New Zealand, in 1977. This cohort has now been studied from birth to the age of 35. SCOPE OF THIS REVIEW: This article examines a series of findings from the CHDS that address a range of issues relating to the use of cannabis amongst the cohort. These issues include: (a) patterns of cannabis use and cannabis dependence; (b) linkages between cannabis use and adverse educational and economic outcomes; (c) cannabis and other illicit drug use; (d) cannabis and psychotic symptoms; (e) other CHDS findings related to cannabis; and (f) the consequences of cannabis use for adults using cannabis regularly. FINDINGS: In general, the findings of the CHDS suggest that individuals who use cannabis regularly, or who begin using cannabis at earlier ages, are at increased risk of a range of adverse outcomes, including: lower levels of educational attainment; welfare dependence and unemployment; using other, more dangerous illicit drugs; and psychotic symptomatology. It should also be noted, however, that there is a substantial proportion of regular adult users who do not experience harmful consequences as a result of cannabis use. CONCLUSIONS: Collectively, these findings suggest that cannabis policy needs to be further developed and evaluated in order to find the best way to regulate a widely-used, and increasingly legal substance.

Tobacco smoking and cannabis use in a longitudinal birth cohort: evidence of reciprocal causal relationships.

BACKGROUND: There is evidence of associations between tobacco and cannabis use that are consistent with both a classical stepping-stone scenario that posits the transition from tobacco use to cannabis use ('gateway' effect of tobacco) and with the reverse process leading from cannabis use to tobacco abuse ('reverse gateway' effect of cannabis). The evidence of direct causal relationships between the two disorders is still missing. METHODS: We analysed data from the Christchurch Health and Development Study (CHDS) longitudinal birth cohort using advanced statistical modelling to control for fixed sources of confounding and to explore causal pathways. The data were analysed using both: (a) conditional fixed effects logistic regression modelling; and (b) a systematic structural equation modelling approach previously developed to investigate psychiatric co-morbidities in the same cohort. RESULTS: We found significant (p<0.05) associations between the extent of cannabis use and tobacco smoking and vice versa, after controlling for non-observed fixed confounding factors and for a number of time-dynamic covariate factors (major depression, alcohol use disorder, anxiety disorder, stressful life events, deviant peer affiliations). Furthermore, increasing levels of tobacco smoking were associated with increasing cannabis use (p=0.02) and vice versa (p<0.001) over time. CONCLUSIONS: Our results lend support to the notion of both of 'gateway' and 'reverse gateway' effects. That is, the association between tobacco and cannabis use arises from a reciprocal feedback loop involving simultaneous causation between tobacco use disorder and cannabis use disorder.

Impact of a major disaster on the mental health of a well-studied cohort.

IMPORTANCE: There has been growing research into the mental health consequences of major disasters. Few studies have controlled for prospectively assessed mental health. This article describes a natural experiment in which 57% of a well-studied birth cohort was exposed to a major natural disaster (the Canterbury, New Zealand, earthquakes in 2010-2011), with the remainder living outside of the earthquake area. OBJECTIVE: To examine the relationships between the extent of earthquake exposure and mental health outcomes following the earthquakes-net of adjustment for potentially confounding factors related to personal circumstances, prior mental health, and childhood family background. DESIGN, SETTING, AND PARTICIPANTS: Data were gathered from the Christchurch Health and Development Study, a 35-year longitudinal study of a birth cohort of New Zealand children (635 males and 630 females). This general community sample included 952 participants with available data on earthquake exposure and mental health outcomes at age 35 years. EXPOSURES: A composite measure of exposure to the events during and subsequent to the 4 major (Richter Scale >6.0) Canterbury earthquakes during the years 2010-2011. MAIN OUTCOMES AND MEASURES: DSM-IV symptom criteria for major depression; posttraumatic stress disorder; anxiety disorder; suicidal ideation/attempt; nicotine dependence; alcohol abuse/dependence; and illicit drug abuse/dependence. Outcomes were measured approximately 20 to 24 months after the onset of exposure to the earthquakes and were assessed using DSM-IV diagnostic criteria and measures of subclinical symptoms. RESULTS: After covariate adjustment, cohort members with high levels of exposure to the earthquakes had rates of mental disorder that were 1.4 (95% CI, 1.1-1.7) times higher than those of cohort members not exposed. This increase was due to increases in the rates of major depression; posttraumatic stress disorder; other anxiety disorders; and nicotine dependence. Similar results were found using a measure of subclinical symptoms (incidence rate ratio, 1.4; 95% CI, 1.1-1.6). Estimates of attributable fraction suggested that exposure to the Canterbury earthquakes accounted for 10.8% to 13.3% of the overall rate of mental disorder in the cohort at age 35 years. CONCLUSIONS AND RELEVANCE: Following extensive control for prospectively measured confounding factors, exposure to the Canterbury earthquakes was associated with a small to moderate increase in the risk for common mental health problems.

Childhood socio-economic status and ethnic disparities in psychosocial outcomes in New Zealand.

OBJECTIVE: The present study examined the extent to which childhood socio-economic status (SES) could account for differences in adult psychosocial outcomes between Maori and non-Maori individuals in a birth cohort of more than 1000 individuals studied to age 30. METHODS: Data were gathered on three measures of childhood SES (family SES, family living standards, family income) and adult psychosocial outcomes including mental health, substance use, criminal offending, and education/welfare dependence outcomes, as part of a longitudinal study of a New Zealand birth cohort (the Christchurch Health and Development Study). RESULTS: Those reporting Maori ethnicity had significantly (p < 0.0001) poorer scores on the three measures of childhood SES, with estimates of Cohen's d indicating a moderate effect size. Maori cohort members also had significantly (p < 0.05) greater rates of adverse psychosocial outcomes in adulthood. Controlling for childhood SES reduced the magnitude of the ethnic differences in psychosocial outcomes, but did not fully explain the differences between Maori and non-Maori. Adjustment for childhood SES had the strongest effect on education/welfare dependence, but weaker effects on mental health, substance use, and criminal offending. CONCLUSIONS: Improvements in SES among Maori in New Zealand may, to some extent, ameliorate the long standing disparities in psychosocial well-being between Maori and non-Maori. However, efforts to improve Maori well-being will require an approach that moves beyond a sole focus on rectifying socio-economic disadvantage.

Moderating role of the MAOA genotype in antisocial behaviour.

BACKGROUND: Recent studies have examined gene×environment (G×E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between exposure to adversity and antisocial behaviour. The present study examined a novel method for assessing interactions between a single gene and multiple risk factors related to environmental and personal adversity. AIMS: To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to a series of risk factors. METHOD: Participants were 399 males from the Christchurch Health and Development Study who had complete data on: (a) MAOA promoter region variable number tandem repeat genotype; (b) antisocial behaviour (criminal offending) to age 30 and convictions to age 21; and (c) maternal smoking during pregnancy, IQ, childhood maltreatment and school failure. RESULTS: Poisson regression models were fitted to three antisocial behaviour outcomes (property/violent offending ages 15-30; and convictions ages 17-21), using measures of exposure to adverse childhood circumstances. The analyses revealed consistent evidence of G x E interactions, such that those with the low-activity MAOA variant who were exposed to adversity in childhood were significantly more likely to report offending in late adolescence and early adulthood. CONCLUSIONS: The present findings add to the evidence suggesting that there is a stable G x E interaction involving MAOA, a range of adverse environmental and personal factors, and antisocial behaviour across the life course. These analyses also demonstrate the utility of using multiple environmental/personal exposures to test G×E interactions.

Risk factors for conduct disorder and oppositional/defiant disorder: evidence from a New Zealand birth cohort.

OBJECTIVE: To examine the social, family background, and individual antecedents of conduct disorder (CD) and oppositional defiant disorder (ODD), the extent to which CD and ODD symptoms were predicted by common environmental risk factors, and the extent to which the antecedents of CD and ODD accounted for the comorbidity between the two disorders. METHOD: Data were gathered from 926 members of a New Zealand longitudinal birth cohort. The outcome measures were DSM-IV symptom count measures of CD and ODD at age 14 to 16 years. Predictors measured during the period from 0 to 14 years included the following: maternal smoking during pregnancy; exposure to socioeconomic adversity; parental maladaptive behavior; childhood exposure to abuse and interparental violence; gender; cognitive ability; and affiliation with deviant peers in early adolescence. Associations between the predictors and outcome measures were modeled using structural equation modeling. RESULTS: The analyses showed that each of the predictors was significantly (p < .05) associated with CD and ODD, with the exception of gender and ODD. After model fitting, the profile of risk factors that predicted CD and ODD were largely similar. The analyses revealed that approximately 40% of the comorbidity between disorders could be accounted for by common factors. CONCLUSIONS: The data showed that CD and ODD had largely similar social and environmental antecedents. One implication of this finding is that treatment and prevention approaches that are developed for use with a particular behavior disorder may in fact reduce the incidence of both disorders.

Cigarette smoking and depression: tests of causal linkages using a longitudinal birth cohort.

BACKGROUND: Research on the comorbidity between cigarette smoking and major depression has not elucidated the pathways by which smoking is associated with depression. AIMS: To examine the causal relationships between smoking and depression via fixed-effects regression and structural equation modelling. METHOD: Data were gathered on nicotine-dependence symptoms and depressive symptoms in early adulthood using a birth cohort of over 1000 individuals. RESULTS: Adjustment for confounding factors revealed persistent significant (P<0.05) associations between nicotine-dependence symptoms and depressive symptoms. Structural equation modelling suggested that the best-fitting causal model was one in which nicotine dependence led to increased risk of depression. The findings suggest that the comorbidity between smoking and depression arises from two routes; the first involving common or correlated risk factors and the second a direct path in which smoking increases the risk of depression. CONCLUSIONS: This evidence is consistent with the conclusion that there is a cause and effect relationship between smoking and depression in which cigarette smoking increases the risk of symptoms of depression.

Does socioeconomic inequality explain ethnic differences in nicotine dependence? Evidence from a New Zealand birth cohort.

OBJECTIVE: The present study examined the role of socioeconomic status and cultural identity in the association between ethnicity and nicotine dependence, in a birth cohort of >1000 methods young people studied to age 30. METHODS: Data were gathered on ethnicity, cultural identification, nicotine dependence, and socioeconomic factors, as part of a longitudinal study of a New Zealand birth cohort (the Christchurch Health and Development Study). RESULTS: Those reporting Maori identity had rates of nicotine dependence that were significantly higher (p < 0.05) than rates for non-Maori. Control for socioeconomic factors reduced the associations between ethnic identity and nicotine dependence to statistical non-significance. In addition, there was no evidence of a statistically significant association between Maori cultural identity and nicotine dependence, nor was there evidence of gender differences in the association between ethnic identity and nicotine dependence, after controlling for socioeconomic factors. CONCLUSIONS: The higher rates of nicotine dependence observed among Maori appear to be attributable to differences in socioeconomic status. Efforts to improve the socioeconomic standing of Maori should therefore help to reduce rates of nicotine dependence in this population.

Childhood social disadvantage and smoking in adulthood: results of a 25-year longitudinal study.

AIM: To examine the associations between exposure to socio-economic disadvantage in childhood and smoking in adulthood. DESIGN: A 25-year longitudinal study of the health, development and adjustment of a birth cohort of 1265 New Zealand children. MEASUREMENTS: Assessments of childhood socio-economic disadvantage, smoking in adulthood and potential mediating pathways, including: parental education, family socio-economic status, family living standards and family income; smoking frequency and nicotine dependence at age 25 years; child IQ, educational achievement by age 18 years, conduct problems ages 14-16 years, parental smoking 0-16 years and peer smoking at 16 years. FINDINGS: Smoking at age 25 was correlated significantly (P < 0.0001) with increasing childhood socio-economic disadvantage. Further, indicators of childhood socio-economic disadvantage were correlated significantly (P < 0.0001) with the intervening variables of childhood intelligence, school achievement, conduct problems and exposure to parental and peer smoking; which in turn were correlated significantly (P < 0.0001) with measures of smoking at age 25. Structural equation modelling suggested that the linkages between the latent factor of childhood disadvantage and later smoking were explained largely by a series of pathways involving cognitive/educational factors, adolescent behavioural adjustment and exposure to parental and peer smoking. CONCLUSIONS: The current study suggested that smoking in adulthood is influenced by childhood socio-economic disadvantage via the mediating pathways of cognitive/educational factors, adolescent behaviour and parental and peer smoking.

Illicit drug use and dependence in a New Zealand birth cohort.

OBJECTIVE: To describe the patterns of illicit drug use in a birth cohort studied to the age of 25 years. METHOD: The data were gathered during the Christchurch Health and Development Study. In this study a cohort of 1265 children born in the Christchurch, New Zealand urban region in mid-1977 have been studied to the age of 25 years. Information was gathered on patterns of illicit drug use and dependence during the period 15-25 years. RESULTS: By age 25 years, 76.7% of the cohort had used cannabis, while 43.5% had used other illicit drugs on at least one occasion. In addition, 12.5% of the cohort met DSM-IV criteria for dependence on cannabis, and 3.6% of the cohort met criteria for dependence on other illicit drugs at some time by age 25. There was also evidence of substantial poly-drug use among the cohort, with hallucinogens and amphetamines being the most commonly used illicit drugs (excluding cannabis). Illicit drug use and dependence was higher in males, in Maori, and in those leaving school without qualifications. Key risk factors for illicit drug use and dependence included adolescent risk-taking behaviours including cigarette smoking and alcohol consumption, affiliation with substance-using peers, novelty-seeking, and conduct problems in adolescence. Other key risk factors included parental history of illicit drug use and childhood sexual abuse. CONCLUSIONS: Levels of cumulative illicit drug use in this cohort were relatively high, with the majority of respondents having tried illicit drugs by age 25. For the majority of illicit drug users, drug use did not lead to problems of dependence. Nonetheless, nearly 15% of the cohort showed symptoms of illicit drug dependence by the age of 25 years, with cannabis dependence accounting for the majority of illicit drug dependence.