Investigation of genetic determinants of cognitive change in later life.

Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10-8 with slope 1) and rs34743896 (p = 5 × 10-10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.

Cognitive functioning in anxiety and depression: results from the ALSPAC cohort.

Anxiety and depression are associated with a range of impairments in cognitive functioning. Understanding the nature of these deficits may identify targets for intervention and prevent functional decline. We used observational and genetic methods to investigate the relationship of anxiety and depression with three cognitive domains: emotion recognition, response inhibition, and working memory, in the Avon Longitudinal Study of Parents and Children (ALSPAC). We examined: (i) cross-sectional associations between anxiety, depression, and cognition at age 24 (n = 2187), (ii) prospective associations between anxiety and depression at age 18 and cognition at age 24 (n = 1855), and (iii) the casual effect of anxiety and depression on cognition using Mendelian randomization (MR). Both disorders were associated with altered emotion recognition; anxiety with decreased happiness recognition (b = -0.27 [-0.54,0.01], p = 0.045), and depression with increased sadness recognition (b = 0.35 [0.07,0.64], p = 0.016). Anxiety was also associated with poorer working memory (b = -0.14 [-0.24,0.04], p = 0.005). There was no evidence for an association with response inhibition. MR provided no clear evidence of causal relationships between mental health and cognition, but these analyses were underpowered. Overall, there was little evidence for impairments in executive functioning, but moderate alterations in emotion recognition. This may inform the development of psychosocial interventions.

Association between inflammation and cognition: Triangulation of evidence using a population-based cohort and Mendelian randomization analyses.

BACKGROUND: Inflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear. METHODS: In a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability. RESULTS: In the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, -0.02 [95 % confidence interval (CI) -0.06 to 0.02, p = 0.27] to 0.02 [95 % CI -0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, -0.73 [95 % CI -2.47 to 1.01, p = 0.41] to 0.21 [95 % CI -1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, -0.02 [95 % CI -0.05 to 0.01, p = 0.12] to 0.03 [95 % CI -0.01 to 0.07, p = 0.19]). CONCLUSIONS: Our MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains.

Examining the bidirectional association between emotion recognition and social autistic traits using observational and genetic analyses.

BACKGROUND: There is mixed evidence for an association between autism spectrum disorder (ASD) and emotion recognition deficits. We sought to assess the bidirectionality of this association using phenotypic and genetic data in a large community sample. METHODS: Analyses were conducted in three stages. First, we examined the bidirectional association between social autistic traits at age 8 years and emotion recognition task (ERT) responses at age 24 years (Study 1; N = 3,562); and between Diagnostic Analysis of Non-Verbal Accuracy (DANVA) emotion recognition responses at age 8 years and social autistic traits at age 10 years (Study 2; N = 9,071). Next, we used genetic analyses (Study 3) to examine the association between polygenic risk scores for ASD and outcomes for the ERT and DANVA. The genetic correlation between ASD and ERT responses at age 24 was also estimated. Analyses were conducted in the Avon Longitudinal Study of Parents and Children. RESULTS: Social autistic traits at age 8 years were negatively associated with later total correct responses on ERT in Study 1 (b = -0.18; 95% CI: -0.27 to -0.09). We also found evidence of an association in Study 2 (b = -0.04; 95% CI: -0.05 to -0.03). We found the opposite association, that is positive, between the ASD polygenic risk score and ERT (b = 0.40; 95% CI: 0.10 to 0.70); however, this association varied across different p-value thresholds and would not survive multiple testing, so should be interpreted with caution. We did not find evidence of a genetic correlation between ASD and ERT. CONCLUSION: We found an observational association between poorer emotion recognition and increased social autistic traits. Our genetic analyses may suggest a shared genetic aetiology between these or a potential causal pathway; however, future research would benefit from using better powered GWAS to examine this further. Our results may inform interventions targeting emotion recognition.

Testing the association between tobacco and cannabis use and cognitive functioning: Findings from an observational and Mendelian randomization study.

BACKGROUND: Although studies have examined the association between tobacco and cannabis use in adolescence with subsequent cognitive functioning, study designs are usually not able to distinguish correlation from causation. METHODS: Separate patterns of tobacco and cannabis use were derived using longitudinal latent class analysis based on measures assessed on five occasions from age 13-18 in a large UK population cohort (Avon Longitudinal Study of Parents and Children). Cognitive functioning measures comprised of working memory, response inhibition, and emotion recognition assessed at 24 years of age. Mendelian randomization was used to examine the possible causal relationship between smoking initiation, lifetime cannabis use and cognitive functioning. RESULTS: We found evidence of a relationship between tobacco and cannabis use and diminished cognitive functioning for each of the outcomes in the observational analyses. There was evidence to suggest that late-onset regular tobacco smokers (b=-0.29, 95 %CI=-0.45 to -0.13), early-onset regular tobacco smokers (b=-0.45, 95 %CI=-0.84 to -0.05), and early-onset regular cannabis users (b=-0.62, 95 %CI=-0.93 to -0.31) showed poorer working memory. Early-onset regular tobacco smokers (b = 0.18, 95 %CI = 0.07 to 0.28), and early-onset regular cannabis users (b = 0.30, 95 %CI = 0.08 to 0.52) displayed poorer ability to inhibit responses. Late-onset regular (b=-0.02, 95 %CI=-0.03 to - 0.00), and early-onset regular tobacco smokers (b=-0.04, 95 %CI=-0.08 to -0.01) showed poorer ability to recognise emotions. Mendelian randomization analyses were imprecise and did not provide additional support for the observational results. CONCLUSION: There was some evidence to suggest that adolescent tobacco and cannabis use were associated with deficits in working memory, response inhibition and emotion recognition. Better powered genetic studies are required to determine whether these associations are causal.

Alcohol use and cognitive functioning in young adults: improving causal inference.

BACKGROUND AND AIMS: There have been few longitudinal studies of association between alcohol use and cognitive functioning in young people. We aimed to examine whether alcohol use is a causal risk factor for deficient cognitive functioning in young adults. DESIGN: Linear regression was used to examine the relationship between longitudinal latent class patterns of binge drinking and subsequent cognitive functioning. Two-sample Mendelian randomization (MR) tested evidence for the causal relationship between alcohol use and cognitive functioning. SETTING: South West England. PARTICIPANTS: The observational study included 3155 adolescents and their parents (fully adjusted models) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Genetic instruments for alcohol use were based on almost 1 000 000 individuals from the genome-wide association studies (GWAS) and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Genome-wide association studies for cognitive outcomes were based on 2500 individuals from ALSPAC. MEASUREMENTS: Binge drinking was assessed at approximately 16, 17, 18, 21 and 23 years. Cognitive functioning comprised working memory, response inhibition and emotion recognition assessed at 24 years of age. Ninety-nine independent genome-wide significant single nucleotide polymorphisms (SNPs) associated with 'number of drinks per week' were used as the genetic instrument for alcohol consumption. Potential confounders were included in the observational analyses. FINDINGS: Four binge drinking classes were identified: 'low-risk' (41.3%), 'early-onset monthly' (19.1%), 'adult frequent' (22.5%) and 'early-onset frequent' (17.0%). The association between early-onset frequent binge drinking and cognitive functioning: working memory (b = -0.42, 95% confidence interval (CI) = -1.24 to 0.41), response inhibition (b = 31.9, 95% CI = -25.3 to 89.2), and emotion recognition (b = 0.02, 95% CI = -0.07 to 0.10) in comparison to low-risk drinkers were inconclusive as to whether a difference was present. Two-sample MR analyses similarly provided little evidence that alcohol use is associated with deficits in working memory using the inverse variance weight (b = 0.29, 95% CI = -0.42 to 0.99), response inhibition (b = -0.32, 95% CI = -1.04 to 0.39) and emotion recognition (b = 0.03, 95% CI = -0.55 to 0.61). CONCLUSIONS: Binge drinking in adolescence and early adulthood may not be causally related to deficiencies in working memory, response inhibition or emotion recognition in youths.

Alcohol consumption and internalising disorders in young adults of ALSPAC: a population-based study.

INTRODUCTION: Depression and harmful alcohol consumption contribute significantly to the global health burden, but in young adults, this relationship is under-researched and conflicted. The aim of this study was to determine the sex-based prevalence and the association between internalising disorders such as depression and alcohol use disorders. METHOD: Using the Avon Longitudinal Study of Parents and Children, we assessed the sex-specific prevalence of International Classification of Diseases,Tenth Revision diagnosed generalised anxiety disorder (GAD), depression and fear-based anxieties (FBA) at 24 years (n=3572). We examined the association between internalising disorders and alcohol consumption using the Alcohol Use Disorder Identification Test for Consumption 5+ threshold and Diagnostic and Statistical Manual on Mental Disorders defined criteria for alcohol dependence. RESULTS: Women reported more GAD (11.6% vs 6.5%), depression (13.4% vs 6.9%) and FBA (1.3% vs 0.5%) than men (p<0.001). Harmful drinking, after adjustment for sex and socioeconomic status, was associated with a higher prevalence of depression (OR 1.8, 95% CI 1.3 to 2.4, p<0.001), anxiety (OR 1.4, 95% CI 1.0 to 2.0, p<0.001) and FBA (OR 2.4, 95% CI 1.04 to 5.56, p=0.009) compared with lower-risk drinkers. In contrast, hazardous drinking was associated with a lower prevalence of GAD (OR 0.69, 95% CI 0.54 to 0.88) and depression (OR 0.68, 95% CI 0.54 to 0.86) compared with lower-risk drinkers. CONCLUSIONS: Young adults in the UK who drink harmfully are more likely to have depression and other internalising disorders. Further research should test whether there is a J-shaped relationship between alcohol consumption and mental health in young people and whether this varies across the life course.

Externalising pathways to alcohol-related problems in emerging adulthood.

BACKGROUND: Both 'early-onset persistent' and 'adolescent-onset' conduct problems (CPs) are associated with alcohol-related problems in emerging adulthood. The escalation of early CPs into criminal behaviour and heavy alcohol consumption prior to emerging adulthood are both likely to be important pathways. METHODS: Data were analysed from 3,038 young people in a UK birth cohort, the Avon Longitudinal Study of Parents and Children. The exposure was developmental trajectories of CPs ('low', 'childhood-limited', 'adolescent-onset' and 'early-onset persistent') between ages 4 and 13 years. The mediator was latent classes representing heavy alcohol consumption and/ or criminal behaviour at age 15 years. For the outcome, a quadratic latent growth curve was estimated to capture nonlinear change in alcohol-related problems between ages 18 and 23 years. RESULTS: Those with 'early-onset persistent' [b(95% CI) = 1.16 (0.17, 2.14)] and 'adolescent-onset' CPs [b(95% CI) = 1.31 (0.17, 2.45)] had higher levels of alcohol-related problems at age 18 years compared to those with 'low' CPs', but there was little evidence of an association with alcohol-related problems after age 19 years. There was evidence for an indirect effect of 'early-onset persistent' CPs [b(95% CI) = 1.12 (0.52, 1.72)] on alcohol-related problems at age 18 years via the latent classes of alcohol and criminal behaviour in adolescence. This was not found for 'adolescent-onset' CPs [b(95% CI) = 0.35 (-0.36, 1.07)]. CONCLUSIONS: Strong associations exist between early CPs, adolescent alcohol consumption and criminal behaviour and alcohol-related problems at age 18 years. Associations between early CPs and alcohol-related problems weakened considerably across emerging adulthood.

The effect of parental drinking on alcohol use in young adults: the mediating role of parental monitoring and peer deviance.

BACKGROUND AND AIMS: Evidence demonstrating an association between parental alcohol use and offspring alcohol use from robust prospective studies is lacking. We tested the direct and indirect associations between parental and young adult alcohol use via early alcohol initiation, parental monitoring and associating with deviant peers. DESIGN: Prospective birth cohort study. Path analysis was used to assess the possible association between parental alcohol use (assessed at 12 years) and alcohol use in young adults (assessed at 18 years) via potential mediators (assessed at 14 and 15.5 years, respectively). SETTING: South West England. PARTICIPANTS: Data were available on 3785 adolescents and their parents from the Avon Longitudinal Study of Parents and Children. MEASUREMENTS: The continuous Alcohol Use Disorders Identification Test (AUDIT) score was used as the primary outcome measure. Maternal alcohol use was defined as light (< 4 units on any day), moderate (≥ 4 units on 1-3 days) and high-risk (≥ 4 units on ≥ 4 days in 1 week). Partner alcohol use was also defined as light, moderate and high risk. Socio-economic variables were included as covariates. FINDINGS: There was strong evidence of a total effect from maternal alcohol use to young adult alcohol use [moderate: b = 1.07, 95% confidence interval (CI) = 0.64, 1.49, P < 0.001; high risk: b = 1.71, 95% CI = 1.07, 2.35, P < 0.001]. The majority of this association was explained through early alcohol initiation (moderate: b = 0.14, 95% CI = 0.04, 0.25, P = 0.01; high risk: b = 0.24, 95% CI = 0.07, 0.40, P < 0.01) and early alcohol initiation/associating with deviant peers (moderate: b = 0.06, 95% CI = 0.02, 0.10, P < 0.01; high risk: b = 0.10, 95% CI = 0.03, 0.16, P < 0.01). There was strong evidence of a remaining direct effect (moderate: b = 0.81, 95% CI = 0.39, 1.22, P < 0.001; high risk: b = 1.28, 95% CI = 0.65, 1.91, P < 0.001). A similar pattern of results was evident for partner alcohol use. CONCLUSIONS: Young adults whose parents have moderate or high-risk alcohol consumption are more likely to consume alcohol than those with parents with lower alcohol consumption. This association appears to be partly accounted for by earlier alcohol use initiation and higher prevalence of association with deviant peers.

Educational and emotional health outcomes in adolescence following maltreatment in early childhood: A population-based study of protective factors.

Although childhood maltreatment is associated with long-term impairment, some children function well despite this adversity. This study aimed to identify the key protective factors for good educational attainment and positive emotional health in adolescents who experienced maltreatment in early childhood. Data were analyzed from the Avon Longitudinal Study of Parents and Children, a large UK prospective cohort study. The sample was defined by maternally reported exposure to physical or emotional maltreatment by a parent prior to 5 years. 1118 (8.0%) children were emotionally maltreated and 375 (2.7%) were physically maltreated before the age of 5. There were too few cases of sexual abuse to be considered. Positive outcomes were operationalized as achieving 5 or more grade A*-C GCSE exam grades at 16 years and scores above the cohort median on the self-report Warwick-Edinburgh Mental Wellbeing Scale and Bachmann Self-Esteem Scale at 17.5 years. The associations of individual, family and community covariates with successful adaptation to the adversity of maltreatment were investigated using logistic regression. School related factors, including engagement in extracurricular activities, satisfaction with school and not being bullied were the most important in facilitating resilience in educational attainment, self-esteem and wellbeing. Good communication and social skills was the most protective individual trait. There was insufficient evidence to suggest that family factors were associated with resilience to maltreatment. School-based interventions are recommended to promote positive adaptation following parental maltreatment. Future research should evaluate outcomes across the life-course to understand whether the protective influences of school persist into adulthood.

Resilience in high-risk adolescents of mothers with recurrent depressive disorder: The contribution of fathers.

This study examines the role of paternal emotional support as a resilience promoter in offspring of mothers with depression by considering the role of fathers' mental health and the quality of the couple relationship. Two hundred and sixty-five mothers with recurrent unipolar depression, partners and adolescents from Wales were assessed. Paternal emotional support, couple relationship quality, and paternal depression were assessed at baseline; adolescent mental health symptoms were assessed using the Child and Adolescent Psychiatric Assessment at follow-up. Results showed evidence of an indirect pathway whereby couple relationship quality predicted paternal emotional support (ß = -.21, 95% CI [-.34, -.08]; p = .002) which in turn predicted adolescent depression (ß = -.18, 95% CI [-.33, -.04]; p = .02), but not disruptive behaviours (ß = -.08, 95% CI [-.22, .07]; p = .30), after controlling for relevant confounders. The findings highlight that fathers and the broader family system play an important role in enhancing resilience to depression symptoms in at-risk adolescents.

Alcohol Use in Adolescence and Later Working Memory: Findings From a Large Population-Based Birth Cohort.

AIMS: The study aimed to examine the association between adolescent alcohol use and working memory (WM) using a large population sample. METHODS: Data from the Avon Longitudinal Study of Parents and Children were used to investigate the association between alcohol use at age 15 years and WM 3 years later, assessed using the N-back task (N ~ 3300). A three-category ordinal variable captured mutually exclusive alcohol groupings ranging in order of severity (i.e. low alcohol users, frequent drinkers and frequent/binge drinkers). Differential dropout was accounted for using multiple imputation and inverse probability weighting. Adjustment was made for potential confounders. RESULTS: There was evidence of an association between frequent/binge drinking (compared to the low alcohol group) and poorer performance on the 3-back task after adjusting for sociodemographic confounding variables, WM at age 11 years, and experience of a head injury/unconsciousness before age 11 years (ß = -0.23, 95% CI = -0.37 to -0.09, P = 0.001). However, this association was attenuated (ß = -0.12, 95% CI = -0.27 to 0.03, P = 0.11) when further adjusted for baseline measures of weekly cigarette tobacco and cannabis use. Weaker associations were found for the less demanding 2-back task. We found no evidence to suggest frequent drinking was associated with performance on either task. CONCLUSIONS: We found weak evidence of an association between sustained heavy alcohol use in mid-adolescence and impaired WM 3 years later. Although we cannot fully rule out the possibility of reverse causation, several potential confounding variables were included to address the directionality of the relationship between WM and alcohol use problems.

Low resting heart rate, sensation seeking and the course of antisocial behaviour across adolescence and young adulthood.

BACKGROUND: Low resting heart rate (RHR) is a consistent biological correlate of antisocial behaviour (ASB), however potential mechanisms have been largely unexplored. We hypothesise that lower RHR will be associated with higher ASB levels in mid-adolescence and persistence into adulthood, and that these associations will be explained, in part, by sensation seeking and callous-unemotional traits. METHODS: ASB was assessed repeatedly with young people from ages 15 to 21 years in a population-based birth cohort (ALSPAC). A longitudinal trajectory was derived and showed ASB decreasing across adolescence before stabilising in early adulthood. RHR was recorded at age 12 years, and mediators were assessed at age 14 years. RESULTS: After adjusting for socio-demographic confounders, there was evidence for a total effect of RHR on ASB levels in mid-adolescence [b(95% CI) = -0.08 (-0.14 to -0.02)], reflecting 0.08 more types of antisocial activity in the last year per 10 fewer heart beats per minute. This effect was almost entirely explained through sensation seeking [b(95% CI) = -0.06 (-0.08 to -0.04)]. After additionally adjusting for child and parent-related confounders, all effects weakened; however, there was still evidence of an indirect effect of RHR, via sensation seeking, on ASB levels in mid-adolescence [b(95% CI) = -0.01 (-0.03 to -0.003)]. There was no evidence for a total effect of RHR on ASB levels in early adulthood, and weak evidence of an indirect effect, via sensation seeking [b(95% CI) = -0.01 (-0.01 to -0.00)]. CONCLUSIONS: Lower RHR in childhood was associated with higher ASB levels in mid-adolescence, indirectly via sensation seeking.

The Association Between Prenatal Stress and Externalizing Symptoms in Childhood: Evidence From the Avon Longitudinal Study of Parents and Children.

BACKGROUND: It has been suggested that prenatal maternal stress may increase the risk of childhood externalizing disorders, yet no large cohort study has investigated this association across a large range of acute stressors. Our objective was to estimate the association between prenatal stressful events and risk of offspring conduct disorder and hyperactivity. METHODS: We used data from 10,184 mother-offspring pairs from the United Kingdom-based Avon Longitudinal Study of Parents and Children. Mothers self-reported 42 prenatal stressful life events at 18 weeks' gestation. Symptoms of conduct disorder and hyperactivity in their offspring were measured at 6, 9, 11, 13, and 16 years of age using the Strengths and Difficulties Questionnaire. The primary outcome was membership in high-symptom trajectories of 1) conduct disorder and 2) hyperactivity throughout childhood, identified using latent class growth modeling. Multinomial logistic regression models estimated the association between prenatal stress and both conduct disorder and hyperactivity, after adjusting for sex, parental education, low birth weight, preterm birth, parental social class, maternal smoking and drinking, maternal mental health, offspring stressful life events, and offspring depressive and anxious symptoms. RESULTS: Those exposed to the highest quartile of prenatal stress were more likely to belong to the high symptom trajectory for hyperactivity (B = 0.46, p < .05) and conduct disorder (B = 0.88, p < .01), respectively. Prenatal stress further demonstrated a positive, dose-response relationship with symptoms of externalizing disorders at independent time points. CONCLUSIONS: The findings suggest that prenatal stressful events may be an independent risk factor for offspring externalizing symptoms, regardless of maternal mental health and offspring internalizing.

Effects of Excessive Alcohol Use on Antisocial Behavior Across Adolescence and Early Adulthood.

OBJECTIVE: Antisocial behavior (ASB) decreases with age in most of the population; however, excessive alcohol use can inhibit the desistance process. This study investigated whether excessive early drinking might slow a young person's overall pattern of crime desistance compared with that of others ("between-person effects") and whether short-term increases in alcohol consumption might result in short-term increases in ASB ("within-person effects"). METHOD: Frequency of ASB and typical alcohol consumption were assessed repeatedly in young people 15 to 21 years old in a population-based birth cohort (Avon Longitudinal Study of Parents and Children). Longitudinal trajectories showed ASB decreasing and alcohol use increasing across adolescence, which stabilized in adulthood. The parallel growth model was re-parameterized to simultaneously estimate the person-specific (or "between-person") and time-specific (or "within-person") influences of alcohol on ASB. RESULTS: Typical alcohol consumption by young people 15 years old was positively associated with ASB cross-sectionally and into young adulthood (i.e., there were between-person effects of initial levels of alcohol consumption on initial [b 1.64, standard error 0.21; p < .001] and final [b 0.53, standard error 0.14; p < .001] levels of ASB). Within-person effects also were identified in early adulthood (b 0.06, standard error 0.02; p = .001), showing that when a young person reported consuming more alcohol than normal across the past year, that person also reported engaging in higher than usual levels of ASB. CONCLUSION: The results are consistent with between- and within-person effects of excessive alcohol use on ASB desistence. Future research should further investigate this relation by investigating pathways into excessive alcohol use and ASB in adolescence.

Parental alcohol use and risk of behavioral and emotional problems in offspring.

OBJECTIVE: The majority of studies that have examined parental alcohol use and offspring outcomes have either focused on exposure in the antenatal period or from clinical populations. This study sought to examine proximal and distal associations between parental alcohol use and offspring conduct problems and depressive symptoms in a population birth cohort. METHODS: We used prospective data from a large UK based population cohort (ALSPAC) to investigate the association between parental alcohol use, measured in units, (assessed at ages 4 and 12 years) with childhood conduct trajectories, (assessed on six occasions from 4 to 13.5 years, n = 6,927), and adolescent depressive symptoms (assessed on four occasions from ~13 to ~18 years, n = 5,539). Heavy drinking was defined as ≥21 units per week in mothers and partners who drank 4+ units daily. RESULTS: We found little evidence to support a dose response association between parental alcohol use and offspring outcomes. For example, we found insufficient evidence to support an association between maternal alcohol use at age 4 years and childhood conduct problems (childhood limited: OR = 1.00, 95% CI = .99, 1.01; adolescent onset: OR = 0.99, 95% CI = .98, 1.00; and early-onset persistent: OR = 0.99, 95% CI = .98, 1.00) per 1-unit change in maternal alcohol use compared to those with low levels of conduct problems. We also found insufficient evidence to support an association between maternal alcohol use at age 4 years and adolescent depressive symptoms (intercept: b = .001, 95% CI = -.01, .01, and slope: b = .003, 95% CI = -.03, .03) per 1-unit change in maternal alcohol use. Results remained consistent across amount of alcohol consumed (i.e., number of alcohol units or heavy alcohol use), parent (maternal self-reports or maternal reports of partner's alcohol use), and timing of alcohol use (assessed at age 4 or age 12 years). CONCLUSIONS: There is no support for an association between parental alcohol use during childhood and conduct and emotional problems during childhood or adolescence.

Polygenic Risk, Personality Dimensions, and Adolescent Alcohol Use Problems: A Longitudinal Study.

OBJECTIVE: Alcohol use problems are common during adolescence and can predict serious negative outcomes in adulthood, including substance dependence and psychopathology. The current study examines the notion that alcohol use problems are driven by polygenic influences and that genetic influences may indirectly affect alcohol use problems through multiple pathways of risk, including variations in personality. METHOD: We used a genome-wide approach to examine associations between genetic risk for alcohol use problems, personality dimensions, and adolescent alcohol use problems in two separate longitudinal population-based samples, the Finnish Twin Cohort (FinnTwin12) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were 1,035 young adults from FinnTwin12 and 3,160 adolescents from ALSPAC. Polygenic risk scores (PRS) were calculated for ALSPAC using genome-wide association results (on alcohol dependence symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) from FinnTwin12. A parallel multiple mediator model was tested to examine whether the association between PRS and alcohol use problems assessed at age 16 could be explained by variations in personality dimensions assessed at age 13, including sensation seeking and negative emotionality. RESULTS: PRS were marginally predictive of age 16 alcohol use problems; this association was partially mediated by sensation seeking. Polygenic variation underlying risk for alcohol use problems may directly influence the effects of sensation seeking, which in turn influence the development of alcohol use problems in later adolescence. CONCLUSIONS: These findings contribute to the increasing evidence regarding the salience of sensation seeking during early adolescence as a potential constituent in the risk pathway underlying the development of alcohol use problems.

Stressful Life Events During Pregnancy and Offspring Depression: Evidence From a Prospective Cohort Study.

OBJECTIVE: The fetal programming hypothesis posits that in utero exposure to stress can alter prenatal brain development and lifelong stress response. However, human studies linking objective prenatal stressors to offspring mental illness, especially depression, are rare. The purpose of this study was to examine the association between mothers' exposure to prenatal stressful life events (SLEs) and offspring depression. METHOD: The sample comprised 10,569 members of a prospective population-based cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers reported on the occurrence and impact of 42 prenatal SLEs. Offspring depressive symptoms were assessed using a computerized version of the Clinical Interview Schedule-Revised (CIS-R) at age 17 to 18, as well as 13 self-report statements from the Short Mood and Feelings Questionnaire (SMFQ) at 6 time points from ages 10 to 11 to 18 to 19. Latent class growth analysis (LCGA) was used to identify trajectories of depressive symptoms across adolescence. RESULTS: After adjusting for potential confounders, a 1-unit increase in maternal SLE scores (range, 0-168) during gestation was associated with increased offspring depressive symptoms (ß = 0.07, p < .01) and major depression (odds ratio [OR] = 1.03, 95% CI 1.01, 1.06) at age 17 to 18. LCGA revealed 4 trajectories of depressive symptoms. High maternal SLEs (fourth quartile) were associated with membership in the trajectory characterized by stable, high levels of depression from age 10 to 11 to 18 to 19 years (OR = 1.72, 95% CI = 1.09, 2.71). CONCLUSION: These results provide support for the fetal programming hypothesis, demonstrating that prenatal exposure to acute stress is associated with offspring depression in adolescence. Stress management may be of benefit for expectant mothers.

Examining whether offspring psychopathology influences illness course in mothers with recurrent depression using a high-risk longitudinal sample.

Depression is known to be influenced by psychosocial stressors. For mothers with recurrent depressive illness, the presence of psychopathology in their children may have important effects on their own mental health. Although the impact of maternal depression on child mental health is well-established, no study to date, as far as we are aware, has examined the extent to which offspring psychopathology influences the course of depression in mothers with a history of recurrent depressive illness, what types of child psychopathology impact maternal mental health, or whether risks vary by child gender. Aims were to (a) Use a longitudinal design to examine whether adolescent psychopathology (depression, disruptive behavior disorder; DBD) predicts recurrence of a depressive episode and depression symptom course in women with a history of recurrent depression; and (b) To test if observed effects vary by child gender. 299 mothers with recurrent major depressive disorder and their adolescent offspring were assessed on 2 occasions, 29 months apart. Maternal depression and offspring psychopathology were assessed using semistructured interview measures. Cross-generational links across time were assessed using structural equation modeling. Analyses were adjusted for past severity of maternal depression. Offspring depression symptoms but not DBD symptoms at baseline predicted future episode recurrence in mothers. Depression symptoms in daughters (ß = .16, p = .039) but not sons (ß = -.07, p = .461), predicted an increase in maternal depression symptoms across time. Psychopathology in daughters is associated with long-term depressive symptoms in women (mothers) with a history of recurrent depression. Findings highlight the importance of careful assessment and management of mental health problems in adolescents for more effective management of maternal depression. This study suggests that offspring symptoms of depression may be important for the recurrence of maternal depression episodes. Girls' symptoms of depression may be a particularly important psychosocial stressor for the development of depressive symptoms in mothers with a history of recurrent depression.