Maternal smoking during pregnancy is associated with DNA methylation in early adolescence: A sibling comparison design.

Maternal smoking during pregnancy (MSDP) may impact offspring biological (e.g., deoxyribonucleic acid methylation [DNAm]) and behavioral (e.g., attention-deficit/hyperactivity disorder hyperactive/impulsive [ADHD-HI] symptoms) development. There has been consistency in findings of differential methylation in global DNAm, and the specific genes AHRR, CYP1A1, CNTNAP2, MYO1G, and GFI1 in relation to MSDP. The current study aims to (a) replicate the associations of MSDP and DNAm in prior literature in middle childhood-adolescence (cross-sectionally) using a sibling-comparison design where siblings were discordant for MSDP (n = 328 families; Mage Sibling 1 = 13.02; Sibling 2 = 10.20), adjusting for prenatal and postnatal covariates in order to isolate the MSDP exposure on DNAm. We also (b) cross-sectionally explored the role of DNAm in the most robust MSDP-ADHD associations (i.e., with ADHD-HI) previously found in this sample. We quantified smoking exposure severity for each sibling reflecting time and quantity of MSDP, centered relative to the sibling pair's average (i.e., within-family centered, indicating child-specific effects attributable MSDP exposure) and controlling for the sibling average MSDP (i.e., between-family component, indicating familial confounding related to MSDP). We found that child-specific MSDP was associated with global DNAm, and CNTNAP2, CYP1A1, and MYO1G methylation after covariate adjustment, corroborating emerging evidence for a potentially causal pathway between MSDP and DNAm. There was some evidence that child-specific CNTNAP2 and MYO1G methylation partially explained associations between MSDP and ADHD-HI symptoms, though only on one measure (of two). Future studies focused on replication of these findings in a longitudinal genetic design could further solidify the associations found in the current study. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adolescent substance use and high school noncompletion: exploring the nature of the relationship using a discordant twin design.

BACKGROUND AND AIMS: Previous studies have demonstrated associations between substance use and reduced educational attainment; however, many were unable to account for potential confounding factors like genetics and the rearing environment. In the few studies that controlled for these factors, the substances assessed were limited to alcohol, cannabis, and tobacco. To address these limitations, we examined the relationship between adolescent use of seven kinds of substances, the number of additional substances used, and high school noncompletion within a large sample of Australian twins. DESIGN: A series of two-level generalized mixed effects logistic regressions were conducted to examine associations between adolescent substance use and high school noncompletion. SETTING: Australia. PARTICIPANTS: A total of 9579 adult Australian twins from two cohorts of the Australian Twin Registry. MEASUREMENTS: Assessments of high school completion, childhood major depression, conduct disorder symptoms, substance use initiation, demographics, and parental educational attainment using the Australian version of the Semi-Structured Assessment for the Genetics of Alcoholism. FINDINGS: There were unique within-twin-pair effects of use of sedatives (odds ratio [OR] = 22.39 [95% confidence interval (CI) = 1.18-423.48]) and inhalants/solvents (OR = 10.46 [95% CI = 1.30-84.16]) on high school noncompletion. The number of substances used in adolescence was strongly associated with high school noncompletion across all discordant twin models (ORs from 1.50-2.32, Ps < 0.03). CONCLUSIONS: In Australia, adolescent substance use appears to be associated with early school dropout, with the effects of any given substance largely because of the confounding factors of parental education, childhood conduct disorder symptoms, and use of other substances. Sedatives and inhalants/solvents have effects on high school noncompletion that cannot be explained by polysubstance use or familial factors.

The roles of familial transmission and smoking during pregnancy on executive function skills: A sibling-comparison study.

This research examines maternal smoking during pregnancy and risk for poorer executive function in siblings discordant for exposure. Data (N = 173 families) were drawn from the Missouri Mothers and Their Children study, a sample, identified using birth records (years 1998-2005), in which mothers changed smoking behavior between two pregnancies (Child 1 [older sibling]: M age = 12.99; Child 2 [younger sibling]: M age = 10.19). A sibling comparison approach was used, providing a robust test for the association between maternal smoking during pregnancy and different aspects of executive function in early-mid adolescence. Results suggested within-family (i.e., potentially causal) associations between maternal smoking during pregnancy and one working memory task (visual working memory) and one response inhibition task (color-word interference), with increased exposure associated with decreased performance. Maternal smoking during pregnancy was not associated with stop-signal reaction time, cognitive flexibility/set-shifting, or auditory working memory. Initial within-family associations between maternal smoking during pregnancy and visual working memory as well as color-word interference were fully attenuated in a model including child and familial covariates. These findings indicate that exposure to maternal smoking during pregnancy may be associated with poorer performance on some, but not all skills assessed; however, familial transmission of risk for low executive function appears more important.

Temporal trends in smoking and nicotine dependence in relation to co-occurring substance use in the United States, 2005-2016.

BACKGROUND: Despite an overall decline in tobacco use in the United States, secular trends of smoking and nicotine dependence with co-occurring substance use are not well characterized. METHODS: We examined self-reported tobacco and other substance use in 22,245 participants age 21-59 in the United States from six waves of the National Health and Nutrition Examination Survey (NHANES). Using Joinpoint regression, we assessed secular trends of smoking and nicotine dependence as a function of co-occurring use of alcohol, prescription opioids, marijuana/hashish, cocaine/heroin/methamphetamine, or other injection drug use. Multivariable logistic regressions were fitted to identify the potential risk factors. RESULTS: During 2005-2016, the prevalence of current smoking decreased (without co-occurring substance use: 17.0 %-12.7 %; with co-occurring use of one substance: 35.3 % to 24.6 %; with co-occurring use of two or more substances: 53.8 %-42.2 %), and moderate-to-severe nicotine dependence decreased as well (8.0 %-4.2 %, 16.0 %-8.8 %, and 23.9 %-15.7 %, respectively). Smoking and nicotine dependence were more likely in those with co-occurring use of one substance (current smoking: odds ratio [OR] = 2.22, 95 % confidence interval [CI] = 2.01-2.45); nicotine dependence: OR = 1.88, 95 % CI = 1.63-2.17) and in those with co-occurring use of two or more substances (current smoking: OR = 5.25, 95 % CI = 4.63-5.95; nicotine dependence: OR = 3.24, 95 % CI = 2.72-3.87). CONCLUSIONS: Co-occurring substance use was associated with smaller reductions in tobacco use, over time, and with increased odds of nicotine dependence. This suggests that co-occurring substance users should be regarded as a tobacco-related disparity group and prioritized for tobacco control interventions.

Timing of mortality in mothers with recurrent convictions for driving under the influence of alcohol and their children, from childbirth to child age 17.

BACKGROUND: We tested variation in the timing of child and maternal mortality associated with severe maternal AUD, as represented by recurrent arrests for driving under the influence of alcohol (rDUI). METHODS: rDUI mothers (N = 1614) and Controls with no alcohol-related driving offenses (N = 109,928) who gave birth in Missouri from 2000 to 2004 were identified using vital records. Propensity score matching adjusted for birth record measures including delayed prenatal care, smoking during pregnancy, relationship with reproductive partner [married/unmarried, paternity acknowledged/unacknowledged], partner DUI status from driving records, and for socioeconomic characteristics of maternal residential census tract at birth derived from census data. Survival analysis was used to test months from childbirth to child or maternal death as a function of lifetime rDUI status. RESULTS: Maternal rDUIs were associated with a consistently elevated probability of child mortality from birth through child age 17 after propensity score-adjustment (Hazard Ratio [HR] = 1.70, 95 % CI = 1.17-2.47). Maternal mortality was not elevated, relative to Controls, until child age 6-11 (HR = 1.58, 95 % CI = 1.05-2.35) and increased again from child age 12-17 (HR = 4.12, 95 % CI = 3.04-5.86). CONCLUSIONS: Severe maternal AUD, as characterized by rDUI, increases the risk for child mortality over that of Controls through age 17. Delays in rDUI maternal mortality until child age 6 may indicate a period when maternal referral for intervention to reduce harm to child and mother is likely to be especially effective.

A sibling-comparison study of smoking during pregnancy and risk for reading-related problems.

This research examines the relationship between smoking during pregnancy (SDP) and risk for reading related problems in siblings discordant for exposure to SDP. Data (N = 173 families) were drawn from the Missouri Mothers and Their Children study, a sample, identified using birth records (years 1998-2005), in which mothers changed her smoking behavior between two pregnancies (Child 1 [older sibling]: M = 12.99; Child 2 [younger sibling]: M = 10.19). A sibling comparison approach was used, providing a robust test for the association between SDP and reading related outcomes in school-aged children. Results suggested within-family (i.e., potentially causal) associations between SDP and reading and language/comprehension factor scores, as well as between SDP and specific reading-related skills, including reading accuracy and receptive language, with increased exposure to SDP associated with decreased performance. SDP was not associated with spelling, reading rate, or receptive vocabulary. Initial within-family associations between SDP and word-letter identification, phonetic/decoding skills, and reading comprehension were fully attenuated following partial control for genetic and environmental confounding of the associations. These findings indicate that exposure to SDP is associated with poorer performance on some, but not all skills assessed.

The Effect of Smoking during Pregnancy on Severity and Directionality of Externalizing and Internalizing Symptoms: A Genetically Informed Approach.

The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07, p = 0.04) was observed in the sibling comparison model. The positive directionality score indicates that SDP is associated with differentiation of symptoms towards externalizing rather than internalizing symptoms after controlling for familial confounds with a sibling comparison model. This supports a potentially causal relationship between SDP and externalizing behavior.

Marital status, partner acknowledgment of paternity, and neighborhood influences on smoking during first pregnancy: findings across race/ethnicity in linked administrative and census data.

BACKGROUND: Improving prediction of cigarette smoking during pregnancy (SDP), including differences by race/ethnicity and geography, is necessary for interventions to achieve greater and more equitable SDP reductions. METHODS: Using individual-level data on singleton first births, 2010-2017 (N = 182,894), in a US state with high SDP rates, we predicted SDP risk as a function of reproductive partner relationship (marital status, paternity acknowledgement), maternal and residential census tract sociodemographics, and census tract five-year SDP rate. RESULTS: SDP prevalence was 12.7% (white non-Hispanics, WNH), 6.8% (Black/African Americans, AA), 19.5% (Native American, NA), 4.7% (Hispanic, H), and 2.8% (Asian, AS). In WNH and AA, with similar trends in other groups, after adjustment for non-linear effects of maternal age and education and for census tract risk-factors, there was a consistent risk-ordering of SDP rates by reproductive partner relationship: married/with paternity acknowledged < unmarried/acknowledged < unmarried/unacknowledged < married/unacknowledged. Associations with census tract SDP rate, adjusted for maternal and census tract sociodemographics, were stronger for AA and H (OR 2.65-2.67) than for NA (OR = 1.91), WNH (OR = 1.75), or AS (NS). AA SDP was increased in tracts having a higher proportion of WNH residents and was reduced in comparison with WNH at every combination of age, education and partner relationship. CONCLUSIONS: Inattention to differences by race/ethnicity may obscure SDP risk factors. Despite marked race/ethnic differences in unmarried-partner cohabitation rates, failure to acknowledge paternity emerged as an important and consistent risk-predictor. Census-tract five-year SDP rates have heterogeneous origins, but the association of AA SDP risk with increased racial heterogeneity suggests an important influence of neighbor risk behaviors.

Eating disorders in a community-based sample of women with alcohol use disorder and nicotine dependence.

BACKGROUND: Studies consistently report a higher prevalence of substance use disorders (SUDs) among women with eating disorders than control women. However, limited research exists on the prevalence of eating disorder symptoms and diagnoses in women with SUDs, especially in community-based populations. We examined the prevalence of eating disorder symptoms and diagnosis by the presence or absence of lifetime alcohol use disorder (AUD) and/or nicotine dependence (ND) in a community-based sample of women. METHODS: 3756 women (median age = 22 years) from the Missouri Adolescent Female Twin Study completed a modified semi-structured interview assessing lifetime DSM-IV psychiatric disorders and SUDs. Logistic regression models adjusted for demographic characteristics and other psychopathology, and robust standard errors accounted for the non-independence of twin data. RESULTS: In general, women with comorbid AUD and ND had a higher prevalence of eating disorder symptoms and diagnoses than women with AUD or ND Only, who in turn had a higher prevalence than those without either SUD. After adjustment for covariates, women with AUD and ND had significantly greater risk of broad anorexia nervosa (RRR = 3.17; 99 % CI = 1.35, 7.44), purging disorder (2.59; 1.24, 5.43), and numerous eating disorder symptoms than women with neither disorder. Significant differences emerged between individuals with both AUD and ND versus women with AUD Only or ND Only for some eating disorder symptoms. CONCLUSIONS: Women with lifetime AUD or ND diagnoses are at high risk for eating disorder symptoms and diagnoses, underscoring the importance of assessing eating disorder symptoms among women with these disorders.

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Disruptive Behavior in Siblings Discordant for Exposure to Maternal Smoking During Pregnancy: A Multi-rater Approach.

INTRODUCTION: Maternal smoking during pregnancy (SDP) is associated with disruptive behavior. However, there is debate whether the SDP-disruptive behavior association is a potentially causal pathway or rather a spurious effect confounded by shared genetic and environmental factors. AIMS AND METHODS: The Missouri Mothers and Their Children Study is a sibling comparison study that includes families (n = 173) selected for sibling pairs (aged 7-16 years) discordant for SDP. Critically, the sibling comparison design is used to disentangle the effects of SDP from familial confounds on disruptive behavior. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount of SDP). Multiple informants (parents and teachers) reported on disruptive behavior (i.e., DSM-IV semi-structured interview, the Child Behavior Checklist, and Teacher Report Form). RESULTS: The variability in disruptive behavior was primarily a function of within-family differences (66%-100%). Consistent with prior genetically informed approaches, the SDP-disruptive behavior association was primarily explained by familial confounds (genetic and environmental). However, when using a multi-rater approach (parents and teachers), results suggest a potentially causal effect of SDP on disruptive behavior (b = 0.09, SE = 0.04, p = 0.03). The potentially causal effect of SDP remained significant in sensitivity analyses. DISCUSSION: These findings suggest that familial confounding likely plays a complex role in the SDP-disruptive behavior association when examining both parent and teacher reports of behavior. Importantly, the current study highlights the importance of multiple raters, reflecting a more comprehensive measure of complex behaviors (e.g., disruptive behavior) to examine the teratogenic effects of SDP. IMPLICATIONS: Our study provides additional evidence that controlling for genetic and family factors is essential when examining the effect of SDP on later behavioral problems, as it explains a portion of the association between SDP and later behavioral problems. However, we found a significant association between SDP and disruptive behavior when using a multi-rater approach that capitalizes on both parent and teacher report, suggesting that parent and teacher ratings capture a unique perspective that is important to consider when examining SDP-behavior associations.

Associations between polygenic risk for tobacco and alcohol use and liability to tobacco and alcohol use, and psychiatric disorders in an independent sample of 13,999 Australian adults.

BACKGROUND: Substance use, substance use disorders (SUDs), and psychiatric disorders commonly co-occur. Genetic risk common to these complex traits is an important explanation; however, little is known about how polygenic risk for tobacco or alcohol use overlaps the genetic risk for the comorbid SUDs and psychiatric disorders. METHODS: We constructed polygenic risk scores (PRSs) using GWAS meta-analysis summary statistics from a large discovery sample, GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN), for smoking initiation (SI; N = 631,564), age of initiating regular smoking (AI; N = 258,251), cigarettes per day (CPD; N = 258,999), smoking cessation (SC; N = 312,273), and drinks per week (DPW; N = 527,402). We then estimated the fixed effect of these PRSs on the liability to 15 phenotypes related to tobacco and alcohol use, substance use disorders, and psychiatric disorders in an independent target sample of Australian adults. RESULTS: After adjusting for multiple testing, 10 of 75 combinations of discovery and target phenotypes remained significant. PRS-SI (R2 range: 1.98%-5.09 %) was positively associated with SI, DPW, and with DSM-IV and FTND nicotine dependence, and conduct disorder. PRS-AI (R2: 3.91 %) negatively associated with DPW. PRS-CPD (R2: 1.56 %-1.77 %) positively associated with DSM-IV nicotine dependence and conduct disorder. PRS-DPW (R2: 3.39 %-6.26 %) positively associated with only DPW. The variation of DPW was significantly influenced by sex*PRS-SI, sex*PRS-AI and sex*PRS-DPW. Such interaction effect was not detected in the other 14 phenotypes. CONCLUSIONS: Polygenic risks associated with tobacco use are also associated with liability to alcohol consumption, nicotine dependence, and conduct disorder.

Elevated maternal and child mortality among women with multiple DUI convictions compared with socio-demographically matched controls.

AIMS: To assess whether having multiple convictions for driving while under the influence of alcohol (MDUI) in women is a risk factor for maternal, infant and child mortality. DESIGN: Retrospective cohort design using record linkage, comparing women with MDUI convictions with propensity-matched women without alcohol-related driving offences ascertained through state records, on rates of maternal, infant and child mortality. SETTING: Missouri, United States. PARTICIPANTS: MDUI women (n = 1658) and women with no alcohol-related driving convictions (control, n = 184 252) who gave birth from 2000 to 2004. MEASUREMENTS: Data were obtained from state administrative records and US Census data. The outcomes were maternal, infant and child mortality. The input variable was presence or absence of MDUI convictions. Propensity-matching variables were maternal (smoking during pregnancy, delayed prenatal care, previous child deaths, age at birth, mother Missouri-born, education, pre-pregnancy obesity, marital status), reproductive partner (un-named partner, race/ethnicity, education, DUI status) and census tract (socio-economic advantage, urbanicity) characteristics. FINDINGS: Women with MDUI convictions had higher odds of maternal, infant and child mortality than propensity-matched controls [odds ratio (OR) = 2.65, 95% confidence interval (CI) = 2.07-3.40 and OR = 1.75, 95% CI = 1.17-2.61, respectively]. CONCLUSIONS: Having multiple convictions for driving under the influence of alcohol in women appears to be a risk factor for increased maternal, infant and child mortality.

The interaction of sociodemographic risk factors and measures of nicotine dependence in predicting maternal smoking during pregnancy.

BACKGROUND: Understanding differences in nicotine dependence assessments' ability to predict smoking cessation is complicated by variation in quit attempt contexts. Pregnancy reduces this variation, as each pregnant smoker receives the same strong cessation incentive. Cigarette smoking during pregnancy (SDP) provides a powerful paradigm for analyzing the interplay between nicotine dependence measures and sociodemographics in predicting cessation failure. METHODS: Data from a female twin cohort (median birth year 1980), assessed in teens and early twenties, were merged with birth records to identify those with smoking history who experienced childbirth (N = 1657 births, N = 763 mothers). Logistic regression predicting SDP, as a function of birth record sociodemographic variables, generated a sociodemographic risk-score. Further analysis incorporated the risk-score with data from research interviews on DSM-IV-Nicotine Dependence symptom count, Heaviness of Smoking Index. RESULTS: Low maternal educational level, younger age at childbirth, and being unmarried all contributed risk for SDP. In addition to sociodemographic risk-score, the best predictors of SDP included HSI-score (OR:1.51), their two-way interaction (OR:0.39; reduced impact of dependence at intermediate-high sociodemographic risk), history of ≥ two failed quit attempts (OR:1.38), and a dummy variable for prior pregnancy at time of assessment (OR:1.82). DSM-IV-Nicotine Dependence symptoms underperformed the Heaviness of Smoking Index and did not improve prediction when added to the best model. CONCLUSIONS: The 2-item Heaviness of Smoking Index measure and report of ≥ two failed quit attempts performed best for predicting SDP. The contribution of either nicotine dependence measure to SDP risk was diminished at increased levels of sociodemographic risk.

Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Genome-wide association meta-analysis of age at first cannabis use.

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Moderation of alcohol craving reactivity to drinking-related contexts by individual differences in alcohol sensitivity: An ecological investigation.

Laboratory cue exposure investigations have demonstrated that, relative to drinkers who report a high sensitivity to the pharmacologic effects of alcohol, low-sensitivity (LS) drinkers show exaggerated neurocognitive and behavioral reactivity to alcohol-related stimuli. The current study extends this line of work by testing whether LS drinkers report stronger cravings for alcohol in daily life. Data were from an ecological momentary assessment study in which participants (N = 403 frequent drinkers) carried a palmtop computer for 21 days and responded to questions regarding drinking behavior, alcohol craving, mood states, and situational context. Initial analyses identified subjective states (positive and negative mood, cigarette craving) and contextual factors (bar-restaurant location, weekend, time of day, presence of friend, recent smoking) associated with elevated craving states during nondrinking moments. Effects for nearly all these craving correlates were moderated by individual differences in alcohol sensitivity, such that the associations between situational factors and current alcohol craving were larger among LS individuals (as determined by a questionnaire completed at baseline). Complementary idiographic analyses indicated that self-reported craving increased when the constellation of situational factors more closely resembled individuals' observed drinking situations. Again, this effect was moderated by alcohol sensitivity, with greater craving response increases among LS drinkers. The findings align with predictions generated from theory and laboratory cue exposure investigations and should encourage further study of craving and incentive processes in LS drinkers. (PsycINFO Database Record

Cross-Cultural Comparison of Genetic and Cultural Transmission of Smoking Initiation Using an Extended Twin Kinship Model.

BACKGROUND: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent-offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. METHODS: We examined the role of genetic and environmental factors in individual differences for smoking initiation (SI) using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission, while also estimating the regression of the prevalence of SI on age. A dichotomous lifetime 'ever' smoking measure was obtained from twins and relatives in the 'Virginia 30,000' sample and the 'Australian 25,000'. RESULTS: Results demonstrate that both genetic and environmental factors play a significant role in the liability to SI. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission, and resulting genotype-environment covariance. Age regression of the prevalence of SI was significant. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent-offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age × gene interaction, and (2) social homogamy. Neither of the mechanism provided a significantly better explanation of the data. CONCLUSIONS: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on liability to SI.