Associations between adolescent cannabis use and young-adult functioning in three longitudinal twin studies.

Observational studies have linked cannabis use to an array of negative outcomes, including psychiatric symptoms, cognitive impairment, and educational and occupational underachievement. These associations are particularly strong when cannabis use occurs in adolescence. Nevertheless, causality remains unclear. The purpose of the present study was thus to examine associations between prospectively assessed adolescent cannabis use and young-adult outcomes (psychiatric, cognitive, and socioeconomic) in three longitudinal studies of twins (n = 3,762). Twins reporting greater cumulative cannabis use in adolescence reported higher levels of psychopathology as well as poorer socioeconomic outcomes in young adulthood. However, cannabis use remained associated only with socioeconomic outcomes (i.e., educational attainment, occupational status, and income) in monozygotic-cotwin control analyses, which account fully for shared genetic and environmental confounding. Follow-up analyses examining associations between twin differences in adolescent cannabis use and longitudinal change in academic functioning during the middle- and high-school years provided a possible mechanism for these associations, indicating that greater cannabis use during this period was associated with decreases in grade point average and academic motivation as well as increases in academic problem behavior and school disciplinary problems. Our findings thus suggest that cannabis use in adolescence has potentially causal, deleterious effects on adolescent academic functioning and young-adult socioeconomic outcomes despite little evidence suggesting a strong, causal influence on adult mental health or cognitive ability.

Associations between polygenic risk of substance use and use disorder and alcohol, cannabis, and nicotine use in adolescence and young adulthood in a longitudinal twin study.

BACKGROUND: Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. METHODS: PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. RESULTS: Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. CONCLUSIONS: PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

Pubertal timing and adolescent outcomes: investigating explanations for associations with a genetically informed design.

BACKGROUND: Psychopathology and risky behaviors increase during adolescence, and understanding which adolescents are most at risk informs prevention and intervention efforts. Pubertal timing relative to same-sex, same-age peers is a known correlate of adolescent outcomes among both boys and girls. However, it remains unclear whether this relation is better explained by a plausible causal process or unobserved familial liability. METHODS: We extended previous research by examining associations between pubertal timing in early adolescence (age 14) and outcomes in later adolescence (age 17) in a community sample of 2,510 twins (49% boys, 51% girls). RESULTS: Earlier pubertal timing was associated with more substance use, risk behavior, internalizing and externalizing problems, and peer problems in later adolescence; these effects were small, consistent with previous literature. Follow-up co-twin control analyses indicated that within-twin-pair differences in pubertal timing were not associated with within-twin-pair differences in most adolescent outcomes after accounting for shared familial liability, suggesting that earlier pubertal timing and adolescent outcomes both reflect familial risk factors. Biometric models indicated that associations between earlier pubertal timing and negative adolescent outcomes were largely attributable to shared genetic liability. CONCLUSIONS: Although earlier pubertal timing was associated with negative adolescent outcomes, our results suggests that these associations did not appear to be caused by earlier pubertal timing but were likely caused by shared genetic influences.

Difficulties with emotion regulation as a transdiagnostic mechanism linking child maltreatment with the emergence of psychopathology.

Childhood maltreatment is associated with increased risk for most forms of psychopathology. We examine emotion dysregulation as a transdiagnostic mechanism linking maltreatment with general psychopathology. A sample of 262 children and adolescents participated; 162 (61.8%) experienced abuse or exposure to domestic violence. We assessed four emotion regulation processes (cognitive reappraisal, attention bias to threat, expressive suppression, and rumination) and emotional reactivity. Psychopathology symptoms were assessed concurrently and at a 2-year longitudinal follow-up. A general psychopathology factor (p factor), representing co-occurrence of psychopathology symptoms across multiple internalizing and externalizing domains, was estimated using confirmatory factor analysis. Maltreatment was associated with heightened emotional reactivity and greater use of expressive suppression and rumination. The association of maltreatment with attention bias varied across development, with maltreated children exhibiting a bias toward threat and adolescents a bias away from threat. Greater emotional reactivity and engagement in rumination mediated the longitudinal association between maltreatment and increased general psychopathology over time. Emotion dysregulation following childhood maltreatment occurs at multiple stages of the emotion generation process, in some cases varies across development, and serves as a transdiagnostic mechanism linking child maltreatment with general psychopathology.

Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?

The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such "geroprotective" therapies in humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972-1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.

Quantification of biological aging in young adults.

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

Is low cognitive functioning a predictor or consequence of major depressive disorder? A test in two longitudinal birth cohorts.

Cognitive impairment has been identified as an important aspect of major depressive disorder (MDD). We tested two theories regarding the association between MDD and cognitive functioning using data from longitudinal cohort studies. One theory, the cognitive reserve hypothesis, suggests that higher cognitive ability in childhood decreases risk of later MDD. The second, the scarring hypothesis, instead suggests that MDD leads to persistent cognitive deficits following disorder onset. We tested both theories in the Dunedin Study, a population-representative cohort followed from birth to midlife and assessed repeatedly for both cognitive functioning and psychopathology. We also used data from the Environmental Risk Longitudinal Twin Study to test whether childhood cognitive functioning predicts future MDD risk independent of family-wide and genetic risk using a discordant twin design. Contrary to both hypotheses, we found that childhood cognitive functioning did not predict future risk of MDD, nor did study members with a past history of MDD show evidence of greater cognitive decline unless MDD was accompanied by other comorbid psychiatric conditions. Our results thus suggest that low cognitive functioning is related to comorbidity, but is neither an antecedent nor an enduring consequence of MDD. Future research may benefit from considering cognitive deficits that occur during depressive episodes from a transdiagnostic perspective.

Limited psychological and social effects of lifetime cannabis use frequency: Evidence from a 30-year community study of 4,078 twins.

BACKGROUND: Cannabis use is associated with outcomes like income, legal problems, and psychopathology. This finding rests largely on correlational research designs, which rely at best on statistical controls for confounding. Here, we control for unmeasured confounders using a longitudinal study of twins. METHOD: In a sample of 4,078 American adult twins first assessed decades ago, we used cotwin control mixed effects models to evaluate the effect of lifetime average frequency of cannabis consumption measured on substance use, psychiatric, and psychosocial outcomes. RESULTS: On average, participants had a lifetime cannabis frequency of about one to two times per month, across adolescence and adulthood. As expected, in individual-level analyses, cannabis use was significantly associated with almost all outcomes in the expected directions. However, when comparing each twin to their cotwin, which inherently controls for shared genes and environments, we observed within-pair differences consistent with possible causality in three of the 22 assessed outcomes: cannabis use disorder symptoms (ßW-Pooled = .15, SE = .02, p = 1.7 × 10-22), frequency of tobacco use (ßW-Pooled = .06, SE = .01, p = 1.2 × 10-5), and illicit drug involvement (ßW-Pooled = .06, SE = .02, p = 1.2 × 10-4). Covariate specification curve analyses indicated that within-pair effects on tobacco and illicit drug use, but not cannabis use disorder, attenuated substantially when covarying for lifetime alcohol and tobacco use. CONCLUSIONS: The cotwin control results suggest that more frequent cannabis use causes small increases in cannabis use disorder symptoms, approximately 1.3 symptoms when going from a once-a-year use to daily use. For other outcomes, our results are more consistent with familial confounding, at least in this community population of twins. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Effects of Adolescent Cannabis Use on Psychosocial Functioning: A Critical Review of the Evidence.

Although observational studies have shown that adolescent cannabis use is associated with impairments in important psychosocial domains, including peer, romantic, and parent-child relationships, educational outcomes, adult socioeconomic status, and legal consequences, mechanisms underlying these associations remain largely unclear. Cannabis use may have a deleterious causal effect on functioning, but it is also possible the association may be due to reverse causation or confounding by shared vulnerability factors that account for both cannabis use in adolescence and concurrent and subsequent psychosocial impairment. Causally informative studies that delineate these possibilities, including research using epidemiologic samples and quasi-experimental designs, are critical to move the field forward.

The Effects of Adolescent Cannabis Use on Psychosocial Functioning: A Critical Review of the Evidence.

Although observational studies have shown that adolescent cannabis use is associated with impairments in important psychosocial domains, including peer, romantic, and parent-child relationships, educational outcomes, adult socioeconomic status, and legal consequences, mechanisms underlying these associations remain largely unclear. Cannabis use may have a deleterious causal effect on functioning, but it is also possible the association may be due to reverse causation or confounding by shared vulnerability factors that account for both cannabis use in adolescence and concurrent and subsequent psychosocial impairment. Causally informative studies that delineate these possibilities, including research using epidemiologic samples and quasi-experimental designs, are critical to move the field forward.

Adaptation in Young Military Recruits: Protocol for the Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study.

BACKGROUND: Military services provide a unique opportunity for studying resilience, a dynamic process of successful adaptation (ie, doing well in terms of functioning and symptoms) in response to significant adversity. Despite the tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding the neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential for enhancing the resilience of military service members. OBJECTIVE: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize the trajectories of positive adaptation among young military recruits in response to basic combat training (BCT), a well-defined, uniform, and 10-week period of intense stress (aim 1), and identify promotive and protective processes contributing to individual variations in resilience (aim 2). The secondary objective is to investigate the pathways by which neurobehavioral markers of self-regulation assessed using electroencephalography and magnetic resonance imaging contribute to adaptive trajectories (aim 3). METHODS: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped out for BCT. Participants (N=1201) are assessed at 5 time points over the initial >2 years of military service beginning before BCT (baseline) and followed up at 2 weeks and 6, 12, and 18 months after BCT. Participants complete web-based questionnaires assessing vulnerability and protective factors, mental health, and socioemotional functioning at each time point and a battery of neurocognitive tests at time 0. A subset of participants also complete structured diagnostic interviews and additional self-report measures and perform neurobehavioral tasks before and after BCT during electroencephalography sessions and before BCT only during magnetic resonance imaging sessions. RESULTS: This UG3/UH3 project was initially funded in August 2017, with the UG3 pilot work completed at the end of 2018. The UH3 phase of the project was funded in March 2019. Study enrollment for the UH3 phase began on April 14, 2019, and ended on October 16, 2021. A total of 1201 participants are enrolled in the study. Follow-up data collection for the UH3 phase is ongoing and projected to continue through February 2024. We will disseminate the findings through conferences, webinars, open access publications, and communications with participants and stakeholders. CONCLUSIONS: The ARMOR study provides a rich data set to identify the predictors and mechanisms of resilient and nonresilient outcomes in the context of military stressors, which are intended to empirically inform the development of prevention and intervention strategies to enhance the resilience of military trainees and potentially other young people facing significant life challenges. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51235.

Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study of Adaptation in Young Military Recruits: Protocol and rationale for methods and measures.

Background: Military service provides a unique opportunity for studying resilience, a dynamic process of successful adaptation (i.e., doing well in terms of functioning and symptoms) in response to significant adversity. Despite tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential to enhance the resilience of military service members. Objectives: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize trajectories of positive adaptation among young military recruits in response to Basic Combat Training (BCT), a well-defined, uniform, 10-week period of intense stress (Aim 1) and identify promotive and protective processes contributing to individual variations in resilience (Aim 2). The secondary objective is to investigate pathways by which neurobehavioral markers of self-regulation assessed by electroencephalography (EEG) and magnetic resonance imaging (MRI) contribute to adaptive trajectories (Aim 3). Methods: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped for BCT. Participants (N=1,201) are assessed at five timepoints over the initial 2+ years of military service beginning before BCT (baseline) and followed up at 2 weeks, 6, 12, and 18 months post-BCT. At each time point, participants complete online questionnaires assessing vulnerability and protective factors, mental health and social-emotional functioning, and, at Time 0 only, a battery of neurocognitive tests. A subset of participants also complete structured diagnostic interviews, additional self-report measures, and perform neurobehavioral tasks before and after BCT during EEG sessions, and, at pre-BCT only, during MRI sessions. Results: Study enrollment began April 14, 2019 and ended in October 16, 2021. A total of 1,201 participants are enrolled in the study (68.9% male; mean age = 18.9, SD = 3.0). Follow-up data-collection is ongoing and projected to continue through March 2024. We will disseminate findings through conferences, webinars, open access publications, and communications with participants and stakeholders. Conclusions: Results are expected to elucidate how young military recruits adapt to military stressors during the initial years of military service. Understanding positive adaptation of military recruits in the face of BCT has implications for developing prevention and intervention strategies to enhance resilience of military trainees and potentially other young people facing significant life challenges.

Protein-linked ubiquitin chain structure restricts activity of deubiquitinating enzymes.

The attachment of lysine 48 (Lys(48))-linked polyubiquitin chains to proteins is a universal signal for degradation by the proteasome. Here, we report that long Lys(48)-linked chains are resistant to many deubiquitinating enzymes (DUBs). Representative enzymes from this group, Ubp15 from yeast and its human ortholog USP7, rapidly remove mono- and diubiquitin from substrates but are slow to remove longer Lys(48)-linked chains. This resistance is lost if the structure of Lys(48)-linked chains is disrupted by mutation of ubiquitin or if chains are linked through Lys(63). In contrast to Ubp15 and USP7, Ubp12 readily cleaves the ends of long chains, regardless of chain structure. We propose that the resistance to many DUBs of long, substrate-attached Lys(48)-linked chains helps ensure that proteins are maintained free from ubiquitin until a threshold of ubiquitin ligase activity enables degradation.

Confocal Raman microscopy probing of temperature-controlled release from individual, optically-trapped phospholipid vesicles.

Control of permeability of phospholipid vesicle (liposome) membranes is critical to their applications in analytical sensing, in fundamental studies of chemistry in small volumes, and in encapsulation and release of payloads for site-directed drug delivery. Applications of liposome formulations in drug delivery often take advantage of the enhanced permeability of phospholipid membranes at their gel-to-fluid phase transition, where the release of encapsulated molecules can be initiated by an increase in temperature. Despite numerous successful liposome formulations for encapsulation and release methods to study the kinetics, this process has been limited to investigations of bulk vesicle dispersions, which provide little or no information about the vesicle membrane structure and its relationship to the kinetics of trans-membrane transport. In this work, confocal Raman microscopy is adapted to study temperature-dependent release of a model compound, 3-nitrobenzene sulfonate (3-NBS), from individual optically trapped phospholipid vesicles, while simultaneously monitoring structural changes in the vesicle membrane reported by vibrational modes of phospholipid acyl chains and the local environment of the encapsulated compound. The confocal geometry allows efficient excitation and collection of Raman scattering from a single vesicle, while optical trapping allows more than hour-long observations of the same vesicle. With window factor analysis to resolve component spectra, temperature-controlled release of 3-NBS through vesicle membranes composed of pure 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was measured and compared to transport through a lysolipid-containing membrane specifically formulated for efficient drug delivery.

Sensitive periods in development and risk for psychiatric disorders and related endpoints: a systematic review of child maltreatment findings.

Variation in the mental health of people who have experienced childhood maltreatment is substantial. One hypothesis is that this variation is attributable, in part, to the timing of maltreatment-specifically, whether maltreatment occurs during sensitive periods in development when the brain is maximally sensitive to particular types of environmental input. To determine whether there is scientific consensus around when periods of peak sensitivity occur, we did a systematic review of human observational studies. Although 89 (75%) of the 118 unique cross-sectional or longitudinal cohort studies we identified reported timing effects, no consistent sensitive periods were identified for any of the most studied outcomes. Thus, observational research on childhood maltreatment has yet to converge on a single period (or set of periods) of increased vulnerability. We identified study characteristics that might contribute to these between-study differences and used observations from our Review to suggest a comprehensive set of recommendations for future research.

Alcohol and nicotine polygenic scores are associated with the development of alcohol and nicotine use problems from adolescence to young adulthood.

BACKGROUND AND AIMS: Molecular genetic studies of alcohol and nicotine use have identified many genome-wide association study (GWAS) loci. We measured associations between drinking and smoking polygenic scores (PGS) and trajectories of alcohol and nicotine use outcomes from late childhood to early adulthood, substance-specific versus broader-liability PGS effects, and if PGS performance varied for consumption versus problematic substance use. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We fitted latent growth curve models with structured residuals to scores on measures of alcohol and nicotine use and problems from ages 14 to 34 years. We then estimated associations between the intercept (initial status) and slope (rate of change) parameters and PGSs for drinks per week (DPW), problematic alcohol use (PAU), cigarettes per day (CPD) and ever being a regular smoker (SMK), controlling for sex and genetic principal components. All data were analyzed in the United States. PGSs were calculated for participants of the Minnesota Twin Family Study (n = 3225) using results from the largest GWAS of alcohol and nicotine consumption and problematic use to date. FINDINGS: Each PGS was associated with trajectories of use for their respective substances [i.e. DPW (ßmean = 0.08; ßrange = 0.02-0.12) and PAU (ßmean = 0.12; ßrange = -0.02 to 0.31) for alcohol; CPD (ßmean = 0.08; ßrange = 0.04-0.14) and SMK (ßmean = 0.18; ßrange = 0.05-0.36) for nicotine]. The PAU and SMK PGSs also exhibited cross-substance associations (i.e. PAU for nicotine-specific intercepts and SMK for alcohol intercepts and slope). All identified SMK PGS effects remained as significant predictors of nicotine and alcohol trajectories (ßmean = 0.15; ßrange = 0.02-0.33), even after adjusting for the respective effects of all other PGSs. CONCLUSIONS: Substance use-related polygenic scores (PGSs) vary in the strength and generality versus specificity of their associations with substance use and problems over time. The regular smoking PGS appears to be a robust predictor of substance use trajectories and seems to measure both nicotine-specific and non-specific genetic liability for substance use, and potentially externalizing problems in general.

Editorial: Enduring Mental Health: The High Lifetime Prevalence of Psychiatric Disorder and Emerging Science of Persistent Mental Wellness.

Just how common are "common" mental health problems? For much of the 20th century, psychiatric research and the US health care system seemed to proceed under the assumption that the answer is "not very." It was not until the early 1990s that the United States conducted its first nation-wide survey of mental health problems, the National Comorbidity Survey, which revealed that about half of all adult participants had experienced at least one diagnosable psychiatric disorder in their lifetime, and close to 1 in 3 participants had met criteria for a psychiatric diagnosis in the past 12 months.1 Subsequent longitudinal studies showed that these estimates-although initially surprising-were still too low, and that, with repeated assessments over long follow-up periods, the proportion of people who report at least 1 diagnosable brush with a psychiatric disorder can exceed 80%.2.

Adolescent cannabis use and adult psychoticism: A longitudinal co-twin control analysis using data from two cohorts.

Observational studies have repeatedly linked cannabis use and increased risk of psychosis. We sought to clarify whether this association reflects a causal effect of cannabis exposure or residual confounding. We analyzed data from two cohorts of twins who completed repeated, prospective measures of cannabis use (N = 1544) and cannabis use disorder symptoms (N = 1458) in adolescence and a dimensional measure of psychosis-proneness (the Personality Inventory for DSM-5 Psychoticism scale) in adulthood. Twins also provided molecular genetic data, which were used to estimate polygenic risk of schizophrenia. Both cumulative adolescent cannabis use and use disorder were associated with higher Psychoticism scores in adulthood. However, we found no evidence of an effect of cannabis on Psychoticism or any of its facets in co-twin control models that compared the greater-cannabis-using twin to the lesser-using co-twin. We also observed no evidence of a differential effect of cannabis on Psychoticism by polygenic risk of schizophrenia. Although cannabis use and disorder are consistently associated with increased risk of psychosis, the present results suggest this association is likely attributable to familial confounds rather than a causal effect of cannabis exposure. Efforts to reduce the prevalence and burden of psychotic illnesses thus may benefit from greater focus on other therapeutic targets. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Association of Air Pollution Exposure in Childhood and Adolescence With Psychopathology at the Transition to Adulthood.

Importance: Air pollution exposure damages the brain, but its associations with the development of psychopathology are not fully characterized. Objective: To assess whether air pollution exposure in childhood and adolescence is associated with greater psychopathology at 18 years of age. Design, Setting, and Participants: The Environmental-Risk Longitudinal Twin Study is a population-based cohort study of 2232 children born from January 1, 1994, to December 4, 1995, across England and Wales and followed up to 18 years of age. Pollution data generation was completed on April 22, 2020; data were analyzed from April 27 to July 31, 2020. Exposures: High-resolution annualized estimates of outdoor nitrogen oxides (NOx) and particulate matter with aerodynamic diameter less than 2.5 µm (PM2.5) linked to home addresses at the ages of 10 and 18 years and then averaged. Main Outcomes and Measures: Mental health disorder symptoms assessed through structured interview at 18 years of age and transformed through confirmatory factor analysis into continuous measures of general psychopathology (primary outcome) and internalizing, externalizing, and thought disorder symptoms (secondary outcomes) standardized to a mean (SD) of 100 (15). Hypotheses were formulated after data collection, and analyses were preregistered. Results: A total of 2039 participants (1070 [52.5%] female) had full data available. After adjustment for family and individual factors, each interquartile range increment increase in NOx exposure was associated with a 1.40-point increase (95% CI, 0.41-2.38; P = .005) in general psychopathology. There was no association between continuously measured PM2.5 and general psychopathology (b = 0.45; 95% CI, -0.26 to 1.11; P = .22); however, those in the highest quartile of PM2.5 exposure scored 2.04 points higher (95% CI, 0.36-3.72; P = .02) than those in the bottom 3 quartiles. Copollutant models, including both NOx and PM2.5, implicated NOx alone in these significant findings. NOx exposure was associated with all secondary outcomes, although associations were weakest for internalizing (adjusted b = 1.07; 95% CI, 0.10-2.04; P = .03), medium for externalizing (adjusted b = 1.42; 95% CI, 0.53-2.31; P = .002), and strongest for thought disorder symptoms (adjusted b = 1.54; 95% CI, 0.50-2.57; P = .004). Despite NOx concentrations being highest in neighborhoods with worse physical, social, and economic conditions, adjusting estimates for neighborhood characteristics did not change the results. Conclusions and Relevance: Youths exposed to higher levels of outdoor NOx experienced greater psychopathology at the transition to adulthood. Air pollution may be a nonspecific risk factor for the development of psychopathology.

Polygenic scores for smoking and educational attainment have independent influences on academic success and adjustment in adolescence and educational attainment in adulthood.

Educational success is associated with greater quality of life and depends, in part, on heritable cognitive and non-cognitive traits. We used polygenic scores (PGS) for smoking and educational attainment to examine different genetic influences on facets of academic adjustment in adolescence and educational attainment in adulthood. PGSs were calculated for participants of the Minnesota Twin Family Study (N = 3225) and included as predictors of grades, academic motivation, and discipline problems at ages 11, 14, and 17 years-old, cigarettes per day from ages 14 to 24 years old, and educational attainment in adulthood (mean age 29.4 years). Smoking and educational attainment PGSs had significant incremental associations with each academic variable and cigarettes per day. About half of the adjusted effects of the smoking and education PGSs on educational attainment in adulthood were mediated by the academic variables in adolescence. Cigarettes per day from ages 14 to 24 years old did not account for the effect of the smoking PGS on educational attainment, suggesting the smoking PGS indexes genetic influences related to general behavioral disinhibition. In sum, distinct genetic influences measured by the smoking and educational attainment PGSs contribute to academic adjustment in adolescence and educational attainment in adulthood.