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).

Interactions Between Genetic, Prenatal Substance Use, Puberty, and Parenting are Less Important for Understanding Adolescents' Internalizing, Externalizing, and Substance Use than Developmental Cascades in Multifactorial Models.

This study tested interactions among puberty-related genetic risk, prenatal substance use, harsh discipline, and pubertal timing for the severity and directionality (i.e., differentiation) of externalizing and internalizing problems and adolescent substance use. This is a companion paper to Marceau et al. (2021) which examined the same influences in developmental cascade models. Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 4504 White boys, n = 4287 White girls assessed from the prenatal period through 18.5 years). We hypothesized generally that later predictors would strengthen the influence of puberty-related genetic risk, prenatal substance use exposure, and pubertal risk on psychopathology and substance use (two-way interactions), and that later predictors would strengthen the interactions of earlier influences on psychopathology and substance use (three-way interactions). Interactions were sparse. Although all fourteen interactions showed that later influences can exacerbate or trigger the effects of earlier ones, they often were not in the expected direction. The most robust moderator was parental discipline, and differing and synergistic effects of biological and socially-relevant aspects of puberty were found. In all, the influences examined here operate more robustly in developmental cascades than in interaction with each other for the development of psychopathology and transitions to substance use.

Adolescents hospitalised for suicidality: biomarkers, social and affective predictors: a cohort study.

OBJECTIVES: The present research examines genomics and in vivo dynamics of family context and experienced affect following discharge from psychiatric hospitalisation for suicidal thoughts and behaviours (STBs). The purpose of this paper is to provide an overview of a new model, description of model-guided integration of multiple methods, documentation of feasibility of recruitment and retention and a description of baseline sample characteristics. DESIGN: The research involved a longitudinal, multimethod observational investigation. SETTING: Participants were recruited from an inpatient child and adolescent psychiatric hospital. 194 participants ages 13-18 were recruited following hospitalisation for STB. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants underwent a battery of clinical interviews, self-report assessments and venipuncture. On discharge, participants were provided with a phone with (1) the electronically activated recorder (EAR), permitting acoustic capture later coded for social context, and (2) ecological momentary assessment, permitting assessment of in vivo experienced affect and STB. Participants agreed to follow-ups at 3 weeks and 6 months. RESULTS: A total of 71.1% of approached patients consented to participation. Participants reported diversity in gender identity (11.6% reported transgender or other gender identity) and sexual orientation (47.6% reported heterosexual or straight sexual orientation). Clinical interviews supported a range of diagnoses with the largest proportion of participants meeting criteria for major depressive disorder (76.9%). History of trauma/maltreatment was prevalent. Enrolment rates and participant characteristics were similar to other observational studies. CONCLUSIONS: The research protocol characterises in vivo, real-world experienced affect and observed family context as associated with STB in adolescents during the high-risk weeks post discharge, merging multiple fields of study.

Intergenerational transmission of psychopathology: An examination of symptom severity and directionality.

The present study examined the intergenerational transmission of internalizing and externalizing symptom severity, which indexes comorbidity, and symptom directionality, which indicates differentiation toward externalizing versus internalizing problems. Data are from 854 male and female, same-sex adult twin pairs born between 1926 and 1971 (32-60 years old, M = 44.9 years, SD = 4.9 years) from the Twin and Offspring Study in Sweden and their adolescent offspring (11-22 years old, M = 15.7 years, SD = 2.4 years, 52% female). Children-of-twins models revealed additive (9%) and dominant (45%) genetic and nonshared environmental (47%) influences on twins' symptom severity, and additive genetic (39%) and nonshared environmental (61%) influences on twins' symptom directionality. Both comorbid problems and preponderance of symptoms of a particular - internalizing versus externalizing - spectrum were correlated across parent and child generations, although associations were modest especially for directionality (i.e., transmission of specific symptom type). By interpreting findings alongside a recent study of adolescent twins, we demonstrate that the intergenerational transmission of symptom severity and symptom directionality are both unlikely to be attributable to genetic transmission, are both likely to be influenced by direct phenotypic transmission and/or nonpassive rGE, and the intergenerational transmission of symptom severity is also likely to be influenced by passive rGE.

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.

Associations between depression-relevant genetic risk and youth stress exposure: Evidence of gene-environment correlations.

Familial risk for depression is associated with youth exposure to self-generated dependent stressful life events and independent events that are out of youth's control. Familial risk includes both genetic and environmental influences, raising the question of whether genetic influences, specifically, are associated with youth exposure to both dependent and independent stressful life events. To address this question, this study examined the relation between a genome-wide association study (GWAS)-derived depression-based polygenic risk score (DEP-PRS) and youth experiences of dependent and independent stress. Participants were 180 youth (ages 8 to 14, 52.2% female) of European ancestry and their biological mothers recruited based on the presence versus absence of a history of major depressive disorder (MDD) in the mothers. Youth and mothers were interviewed every 6 months for 2 years regarding the occurrence of stressful life events, which were coded as independent or dependent (self-generated). Results indicated that youth's DEP-PRS and maternal history of MDD were uniquely associated with increased exposure to both dependent and independent events. Similar results were observed when examining major versus minor events separately, with the additional finding of a DEP-PRS × mother MDD interaction for major dependent events such that levels of moderate to severe dependent life stressors were highest among youth with high DEP-PRSs who also had mothers with MDD. These results not only support the presence of depression-relevant gene-environment correlations (rGEs), but also highlight the possibility that rather than only capturing depression-specific genetic liability, GWAS-derived polygenic risk scores may also capture genetic variance contributing to stress exposure. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Multi-type childhood maltreatment exposure and substance use development from adolescence to early adulthood: A GxE study.

BACKGROUND: Childhood maltreatment types can co-occur and are associated with increased substance use during adolescence and early adulthood. There is also a strong genetic basis for substance use which interacts with environmental factors (e.g., childhood maltreatment) to influence substance use phenotype. OBJECTIVE: This research aimed to identify childhood maltreatment sub-groups based on type and chronicity, and their association with substance use change from adolescence to early adulthood, while accounting for the influence of substance use polygenic risk (i.e., genetic risk based on the combined effects of multiple genes). PARTICIPANTS: We used a sample of unrelated European-origin Americans with genetic and childhood maltreatment data (n = 2,664) from the National Longitudinal Study of Adolescent to Adult Health. METHODS: Latent profile analysis was used for sub-group identification and direct and interaction effects were tested for longitudinal trajectories of substance use utilizing generalized estimating equations. RESULTS: Three sub-groups with co-occurring childhood maltreatment exposures were identified: a high sexual abuse sub-group, a high physical abuse sub-group, and a normative sub-group (with low maltreatment exposure). At high polygenic risk, the high physical abuse sub-group had faster increases in substance use over time. In comparison, the high sexual abuse sub-group had faster progression in substance use only at low and medium polygenic risk. CONCLUSIONS: Findings provide initial evidence for biological and environmental differences among maltreatment sub-groups on trajectories of substance use.

A Review of Associations between Externalizing Behaviors and Prenatal Cannabis Exposure: Limitations & Future Directions.

In utero cannabis exposure can disrupt fetal development and increase risk for various behavioral disruptions, including hyperactivity, inattention, delinquent behaviors, and later substance abuse, among others. This review summarizes the findings from contemporary investigations linking prenatal cannabis exposure to the development of psychopathology and identifies the limitations within the literature, which constrain our interpretations and generalizability. These limitations include a lack of genetic/familial control for confounding and limited data examining real world products, the full range of cannabinoids, and motives for use specifically in pregnant women. Taken together, our review reveals the need to continue to improve upon study designs in order to allow researchers to accurately draw conclusions about the development of behavioral consequences of prenatal cannabis exposure. Findings from such studies would inform policy and practices regarding cannabis use during pregnancy and move the field toward developing a comprehensive teratogenic profile of cannabis similar to what is characterized in the prenatal alcohol and tobacco literature.

Interactions between Genetic, Prenatal, Cortisol, and Parenting Influences on Adolescent Substance Use and Frequency: A TRAILS Study.

INTRODUCTION: Dynamic relations between genetic, hormone, and pre- and postnatal environments are theorized as critically important for adolescent substance use but are rarely tested in multifactorial models. This study assessed the impact of interactions of genetic risk and cortisol reactivity with prenatal and parenting influences on both any and frequency of adolescent substance use. METHODS: Data are from the TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective longitudinal, multi-rater study of 2,230 Dutch adolescents. Genetic risk was assessed via 3 substance-specific polygenic scores. Mothers retrospectively reported prenatal risk when adolescents were 11 years old. Adolescents rated their parents' warmth and hostility at age 11. Salivary cortisol reactivity was measured in response to a social stress task at age 16. Adolescents' self-reported cigarette, alcohol, and cannabis use frequency at age 16. RESULTS: A multivariate hurdle regression model showed that polygenic risk for smoking, alcohol, and cannabis predicted any use of each substance, respectively, but predicted more frequent use only for smoking. Blunted cortisol reactivity predicted any use and more frequent use for all 3 outcomes. There were 2 interactions: blunted cortisol reactivity exacerbated the association of polygenic risk with any smoking and the association of prenatal risk with any alcohol use. CONCLUSION: Polygenic risk seems of importance for early use but less so for frequency of use, whereas blunted cortisol reactivity was correlated with both. Blunted cortisol reactivity may also catalyze early risks for substance use, though to a limited degree. Gene-environment interactions play no role in the context of this multifactorial model.

Developmental Cascades from Polygenic and Prenatal Substance Use to Adolescent Substance Use: Leveraging Severity and Directionality of Externalizing and Internalizing Problems to Understand Pubertal and Harsh Discipline-Related Risk.

The current study leveraged the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 4504 White boys, n = 4287 White girls assessed from the prenatal period through 18.5 years of age) to test a developmental cascade from genetic and prenatal substance use through pubertal timing and parenting to the severity of (regardless of type) and directionality (i.e., differentiation) of externalizing and internalizing problems to adolescent substance use. Limited associations of early pubertal timing with substance use outcomes were only observable via symptom directionality, differently for girls and boys. For boys, more severe exposure to prenatal substance use influenced adolescent substance use progression via differentiation towards relatively more pure externalizing problems, but in girls the associations were largely direct. Severity and especially directionality (i.e., differentiation towards relatively more pure externalizing problems) were key intermediaries in developmental cascades from parental harsh discipline with substance use progressions for girls and boys.

DNA methylome perturbations: an epigenetic basis for the emergingly heritable neurodevelopmental abnormalities associated with maternal smoking and maternal nicotine exposure†.

Maternal smoking during pregnancy is associated with an ensemble of neurodevelopmental consequences in children and therefore constitutes a pressing public health concern. Adding to this burden, contemporary epidemiological and especially animal model research suggests that grandmaternal smoking is similarly associated with neurodevelopmental abnormalities in grandchildren, indicative of intergenerational transmission of the neurodevelopmental impacts of maternal smoking. Probing the mechanistic bases of neurodevelopmental anomalies in the children of maternal smokers and the intergenerational transmission thereof, emerging research intimates that epigenetic changes, namely DNA methylome perturbations, are key factors. Altogether, these findings warrant future research to fully elucidate the etiology of neurodevelopmental impairments in the children and grandchildren of maternal smokers and underscore the clear potential thereof to benefit public health by informing the development and implementation of preventative measures, prophylactics, and treatments. To this end, the present review aims to encapsulate the burgeoning evidence linking maternal smoking to intergenerational epigenetic inheritance of neurodevelopmental abnormalities, to identify the strengths and weaknesses thereof, and to highlight areas of emphasis for future human and animal model research therein.

Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry.

INTRODUCTION: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. METHODS: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µâ€Šage = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. RESULTS: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (ß = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. CONCLUSIONS: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk. IMPLICATIONS: These findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Multi-omic and multi-species meta-analyses of nicotine consumption.

Cross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBank N = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the 'model organism geneset' will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5-36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60-31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

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.

Single nucleotide polymorphism heritability and differential patterns of genetic overlap between inattention and four neurocognitive factors in youth.

Theoretical models of attention-deficit/hyperactivity disorder implicate neurocognitive dysfunction, yet neurocognitive functioning covers a range of abilities that may not all be linked with inattention. This study (a) investigated the single nucleotide polymorphism (SNP) heritability (h2SNP) of inattention and aspects of neurocognitive efficiency (memory, social cognition, executive function, and complex cognition) based on additive genome-wide effects; (b) examined if there were shared genetic effects among inattention and each aspect of neurocognitive efficiency; and (c) conducted an exploratory genome-wide association study to identify genetic regions associated with inattention. The sample included 3,563 participants of the Philadelphia Neurodevelopmental Cohort, a general population sample aged 8-21 years who completed the Penn Neurocognitive Battery. Data on inattention was obtained with the Kiddie Schedule of Affective Disorders (adapted). Genomic relatedness matrix restricted maximum likelihood was implemented in genome-wide complex trait analysis. Analyses revealed significant h2SNP for inattention (20%, SE = 0.08), social cognition (13%, SE = 0.08), memory (17%, SE = 0.08), executive function (25%, SE = 0.08), and complex cognition (24%, SE = 0.08). There was a positive genetic correlation (0.67, SE = 0.37) and a negative residual covariance (-0.23, SE = 0.06) between inattention and social cognition. No SNPs reached genome-wide significance for inattention. Results suggest specificity in genetic overlap among inattention and different aspects of neurocognitive efficiency.

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.

Neurofibromatosis Type 1 Implicates Ras Pathways in the Genetic Architecture of Neurodevelopmental Disorders.

The genetic architecture of neurodevelopmental disorders is largely polygenic, non-specific, and pleiotropic. This complex genetic architecture makes the search for specific etiological mechanisms that contribute to neurodevelopmental risk more challenging. Monogenic disorders provide an opportunity to focus in on how well-articulated signaling pathways contribute to risk for neurodevelopmental outcomes. This paper will focus on neurofibromatosis type 1 (NF1), a rare monogenic disorder that is associated with varied neurodevelopmental outcomes. Specifically, this paper will provide a brief overview of NF1 and its phenotypic associations with autism spectrum disorder, attention-deficit/hyperactivity disorder, and specific learning disorders, describe how variation within the NF1 gene increases risk for neurodevelopmental disorders via altered Ras signaling, and provide future directions for NF1 research to help elucidate the genetic architecture of neurodevelopmental disorders in the general population.

Polygenic Influences on Pubertal Timing and Tempo and Depressive Symptoms in Boys and Girls.

This study used polygenic scoring (PGS) to test whether puberty-related genes were correlated with depressive symptoms, and whether there were indirect effects through pubertal maturation. The sample included 8,795 adolescents from the Avon Longitudinal Study of Parents and Children (measures of puberty drawn ages 8-17 years; of depressive symptoms at age 16.5 years). The PGS (derived from a genome-wide meta-analysis of later age at menarche) predicted boys' and girls' later pubertal timing, boys' slower gonadal development, and girls' faster breast development. Earlier perceived breast development timing predicted more depressive symptoms in girls. Findings support shared genetic underpinnings for boys' and girls' puberty, contributing to multiple pubertal phenotypes with differences in how these genetic variants affect boys' and girls' development.

Developmental Pathways from Genetic, Prenatal, Parenting and Emotional/Behavioral Risk to Cortisol Reactivity and Adolescent Substance Use: A TRAILS Study.

Cortisol reactivity is a frequently studied biomarker of substance use, though infrequently examined in adolescence. However, past research provides evidence that multiple developmental influences, including genetics and both prenatal and postnatal environmental influences, contribute both to cortisol reactivity and adolescent substance use. The aim of this study was to assess the impact of these earlier developmental influences on cortisol reactivity to a social stress challenge and adolescent substance use (smoking, alcohol, and marijuana use frequency assessed at age 16 years), using data from the TRacking Adolescents' Individual Lives Survey (TRAILS; N= 2230 adolescents, 51% female). Developmental pathways included polygenic risk, prenatal stress, warm parenting (age 11), and internalizing and externalizing problems (intercepts and change from 11-16 years). Cortisol reactivity was associated with smoking but not alcohol or marijuana use. Externalizing problems were the stronger predictor of adolescent substance use, but internalizing problems also had an important role. Prenatal stress and middle childhood parenting operated via middle childhood externalizing problems, and parenting also operated via trajectories of growth of externalizing problems in predicting adolescent substance use outcomes. Further, there were protective effects of internalizing problems for alcohol and marijuana use in the context of a more comprehensive model. These developmental influences did not attenuate the association of cortisol reactivity and smoking. These findings suggest a need to understand the broader developmental context regarding the impact of internalizing pathways to substance use, and that it is unlikely that cortisol reactivity and smoking are associated solely because of common developmental influences.

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.