Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction.

BACKGROUND: The genetic and environmental influences on human personality and behaviour are a complex matter of ongoing debate. Accumulating evidence indicates that short tandem repeats (STRs) in regulatory regions are good candidates to explain heritability not accessed by genome-wide association studies. METHODS: We tested for associations between the genotypes of four selected repeats and 18 traits relating to personality, behaviour, cognitive ability and mental health in a well-studied longitudinal birth cohort (n = 458-589) using one way analysis of variance. The repeats were a highly conserved poly-AC microsatellite in the upstream promoter region of the T-box brain 1 (TBR1) gene and three previously studied STRs in the activating enhancer-binding protein 2-beta (AP2-ß) and androgen receptor (AR) genes. Where significance was found we used multiple regression to assess the influence of confounding factors. RESULTS: Carriers of the shorter, most common, allele of the AR gene's GGN microsatellite polymorphism had fewer anxiety-related symptoms, which was consistent with previous studies, but in our study this was not significant following Bonferroni correction. No associations with two repeats in the AP2-ß gene withstood this correction. A novel finding was that carriers of the minor allele of the TBR1 AC microsatellite were at higher risk of conduct problems in childhood at age 7-9 (p = 0.0007, which did pass Bonferroni correction). Including maternal smoking during pregnancy (MSDP) in models controlling for potentially confounding influences showed that an interaction between TBR1 genotype and MSDP was a significant predictor of conduct problems in childhood and adolescence (p < 0.001), and of self-reported criminal behaviour up to age 25 years (p ≤ 0.02). This interaction remained significant after controlling for possible confounders including maternal age at birth, socio-economic status and education, and offspring birth weight. CONCLUSIONS: The potential functional importance of the TBR1 gene's promoter microsatellite deserves further investigation. Our results suggest that it participates in a gene-environment interaction with MDSP and antisocial behaviour. However, previous evidence that mothers who smoke during pregnancy carry genes for antisocial behaviour suggests that epistasis may influence the interaction.

Adolescent substance use and educational attainment: An integrative data analysis comparing cannabis and alcohol from three Australasian cohorts.

BACKGROUND: The relative contributions of cannabis and alcohol use to educational outcomes are unclear. We examined the extent to which adolescent cannabis or alcohol use predicts educational attainment in emerging adulthood. METHODS: Participant-level data were integrated from three longitudinal studies from Australia and New Zealand (Australian Temperament Project, Christchurch Health and Development Study, and Victorian Adolescent Health Cohort Study). The number of participants varied by analysis (N=2179-3678) and were assessed on multiple occasions between ages 13 and 25. We described the association between frequency of cannabis or alcohol use prior to age 17 and high school non-completion, university non-enrolment, and degree non-attainment by age 25. Two other measures of alcohol use in adolescence were also examined. RESULTS: After covariate adjustment using a propensity score approach, adolescent cannabis use (weekly+) was associated with 1½ to two-fold increases in the odds of high school non-completion (OR=1.60, 95% CI=1.09-2.35), university non-enrolment (OR=1.51, 95% CI=1.06-2.13), and degree non-attainment (OR=1.96, 95% CI=1.36-2.81). In contrast, adjusted associations for all measures of adolescent alcohol use were inconsistent and weaker. Attributable risk estimates indicated adolescent cannabis use accounted for a greater proportion of the overall rate of non-progression with formal education than adolescent alcohol use. CONCLUSIONS: Findings are important to the debate about the relative harms of cannabis and alcohol use. Adolescent cannabis use is a better marker of lower educational attainment than adolescent alcohol use and identifies an important target population for preventive intervention.

Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.

OBJECTIVES: To investigate, using a Mendelian randomisation approach, whether heavier smoking is associated with a range of regional adiposity phenotypes, in particular those related to abdominal adiposity. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene region) as a proxy for smoking heaviness, of the associations of smoking heaviness with a range of adiposity phenotypes. PARTICIPANTS: 148,731 current, former and never-smokers of European ancestry aged ≥ 16 years from 29 studies in the consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Waist and hip circumferences, and waist-hip ratio. RESULTS: The data included up to 66,809 never-smokers, 43,009 former smokers and 38,913 current daily cigarette smokers. Among current smokers, for each extra minor allele, the geometric mean was lower for waist circumference by -0.40% (95% CI -0.57% to -0.22%), with effects on hip circumference, waist-hip ratio and body mass index (BMI) being -0.31% (95% CI -0.42% to -0.19), -0.08% (-0.19% to 0.03%) and -0.74% (-0.96% to -0.51%), respectively. In contrast, among never-smokers, these effects were higher by 0.23% (0.09% to 0.36%), 0.17% (0.08% to 0.26%), 0.07% (-0.01% to 0.15%) and 0.35% (0.18% to 0.52%), respectively. When adjusting the three central adiposity measures for BMI, the effects among current smokers changed direction and were higher by 0.14% (0.05% to 0.22%) for waist circumference, 0.02% (-0.05% to 0.08%) for hip circumference and 0.10% (0.02% to 0.19%) for waist-hip ratio, for each extra minor allele. CONCLUSIONS: For a given BMI, a gene variant associated with increased cigarette consumption was associated with increased waist circumference. Smoking in an effort to control weight may lead to accumulation of central adiposity.

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.

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

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.

Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs.

IMPORTANCE: Several studies report an association between maternal smoking during pregnancy and offspring conduct disorder. However, past research evidences difficulty in disaggregating prenatal environmental influences from genetic and postnatal environmental influences. OBJECTIVE: To examine the relationship between maternal smoking during pregnancy and offspring conduct problems among children reared by genetically related mothers and genetically unrelated mothers. DESIGN, SETTING, AND PARTICIPANTS: The following 3 studies using distinct but complementary research designs were used: The Christchurch Health and Development Study (a longitudinal cohort study that includes biological and adopted children), the Early Growth and Development Study (a longitudinal adoption-at-birth study), and the Cardiff IVF (In Vitro Fertilization) Study (an adoption-at-conception study among genetically related families and genetically unrelated families). Maternal smoking during pregnancy was measured as the mean number of cigarettes per day (0, 1-9, or 10) smoked during pregnancy. Possible covariates were controlled for in the analyses, including child sex, birth weight, race/ethnicity, placement age, and breastfeeding, as well as maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status. MAIN OUTCOMES AND MEASURE: Offspring conduct problems (age range, 4-10 years) reported by parents or teachers using the behavior rating scales by Rutter and Conners, the Child Behavior Checklist and the Children's Behavior Questionnaire Short Form, and the Strengths and Difficulties Questionnaire. RESULTS: A significant association between maternal smoking during pregnancy and offspring conduct problems was observed among children reared by genetically related mothers and genetically unrelated mothers. Results from a meta-analysis affirmed this pattern of findings across pooled study samples. CONCLUSIONS AND RELEVANCE: Findings across 3 studies using a complement of genetically sensitive research designs suggest that smoking during pregnancy is a prenatal risk factor for offspring conduct problems when controlling for specific perinatal and postnatal confounding factors.

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.

Cannabis use and educational achievement: findings from three Australasian cohort studies.

BACKGROUND: The associations between age of onset of cannabis use and educational achievement were examined using data from three Australasian cohort studies involving over 6000 participants. The research aims were to compare findings across studies and obtain pooled estimates of association using meta-analytic methods. METHODS: Data on age of onset of cannabis use (<15, 15-17, never before age 18) and three educational outcomes (high school completion, university enrolment, degree attainment) were common to all studies. Each study also assessed a broad range of confounding factors. RESULTS: There were significant (p<.001) associations between age of onset of cannabis use and all outcomes such that rates of attainment were highest for those who had not used cannabis by age 18 and lowest for those who first used cannabis before age 15. These findings were evident for each study and for the pooled data, and persisted after control for confounding. There was no consistent trend for cannabis use to have greater effect on the academic achievement of males but there was a significant gender by age of onset interaction for university enrolment. This interaction suggested that cannabis use by males had a greater detrimental effect on university participation than for females. Pooled estimates suggested that early use of cannabis may contribute up to 17% of the rate of failure to obtain the educational milestones of high school completion, university enrolment and degree attainment. CONCLUSIONS: Findings suggest the presence of a robust association between age of onset of cannabis use and subsequent educational achievement.

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.