Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Dietary and Lifestyle Factors of Brain Iron Accumulation and Parkinson's Disease Risk.

Purpose: Iron is an essential nutrient which can only be absorbed through an individual's diet. Excess iron accumulates in organs throughout the body including the brain. Iron dysregulation in the brain is commonly associated with neurodegenerative diseases like Alzheimer's disease and Parkinson's Disease (PD). Our previous research has shown that a pattern of iron accumulation in motor regions of the brain related to a genetic iron-storage disorder called hemochromatosis is associated with an increased risk of PD. To understand how diet and lifestyle factors relate to this brain endophenotype and risk of PD we analyzed the relationship between these measures, estimates of nutrient intake, and diet and lifestyle preference using data from UK Biobank. Methods: Using distinct imaging and non-imaging samples (20,477 to 28,388 and 132,023 to 150,603 participants, respectively), we performed linear and logistic regression analyses using estimated dietary nutrient intake and food preferences to predict a) brain iron accumulation score (derived from T2-Weighted Magnetic Resonance Imaging) and b) PD risk. In addition, we performed a factor analysis of diet and lifestyle preferences to investigate if latent lifestyle factors explained significant associations. Finally, we performed an instrumental variable regression of our results related to iron accumulation and PD risk to identify if there were common dietary and lifestyle factors that were jointly associated with differences in brain iron accumulation and PD risk. Results: We found multiple highly significant associations with measures of brain iron accumulation and preferences for alcohol (factor 7: t=4.02, pFDR=0.0003), exercise (factor 11: t=-4.31, pFDR=0.0001), and high-sugar foods (factor 2: t=-3.73, pFDR=0.0007). Preference for alcohol (factor 7: t=-5.83, pFDR<1×10-8), exercise (factor 11: t=-7.66, pFDR<1×10-13), and high sugar foods (factor 2: t=6.03, pFDR<1×10-8) were also associated with PD risk. Instrumental variable regression of individual preferences revealed a significant relationship in which dietary preferences associated with higher brain iron levels also appeared to be linked to a lower risk for PD (p=0.004). A similar relationship was observed for estimates of nutrient intake (p=0.0006). Voxel-wise analysis of i) high-sugar and ii) alcohol factors confirmed T2-weighted signal differences consistent with iron accumulation patterns in motor regions of the brain including the cerebellum and basal ganglia. Conclusion: Dietary and lifestyle factors and preferences, especially those related to carbohydrates, alcohol, and exercise, are related to detectable differences in brain iron accumulation and alterations in risk of PD, suggesting a potential avenue for lifestyle interventions that could influence risk.

Prospective associations of family conflict with alcohol expectancies in the adolescent brain cognitive development study: effects of race and ethnicity.

Introduction: Alcohol expectancies predict subsequent alcohol use and related problems among adolescents, although predictors of alcohol expectancies remain unclear. This study examined the longitudinal association between family conflict, a sociocultural factor strongly implicated in adolescent alcohol use, and positive and negative alcohol expectancies of adolescents of diverse racial/ethnic backgrounds. Methods: Data were from the Adolescent Brain Cognitive Development Study 4.0 release, a multisite longitudinal study (N = 6,231, baseline age 9-10). Linear mixed-effects regression, with interactions between race/ethnicity and family conflict, tested the association between family conflict and alcohol expectancies, for each racial/ethnicity (e.g., Black vs. non-Black; White vs. non-White). Results: Interactions of family conflict with race/ethnicity in predicting negative and positive alcohol expectancies were statistically significant for models testing Black and White adolescents, but not for Asian, Hispanic, and Other. Family conflict at baseline predicted lower negative alcohol expectancy for Black adolescents (B = -.166, p = 0.033) and positive alcohol expectancy for White adolescents (B = 0.71, p = 0.023) at the year 3 follow-up. All models controlled for sex, age, family socioeconomic status, alcohol expectancies at year 1, and family conflict at year 3. Conclusion: The results indicate that family conflict is a potential risk factor for problematic alcohol expectancies for Black and White adolescents. Although we did not directly compare Black and White adolescents, our findings indicate that family conflict may operate differently for Black and White adolescents. Prevention and intervention efforts targeting family conflict may be relevant for different aspects of alcohol expectancies in Black and White families.

FEMA: Fast and efficient mixed-effects algorithm for large sample whole-brain imaging data.

The linear mixed-effects model (LME) is a versatile approach to account for dependence among observations. Many large-scale neuroimaging datasets with complex designs have increased the need for LME; however LME has seldom been used in whole-brain imaging analyses due to its heavy computational requirements. In this paper, we introduce a fast and efficient mixed-effects algorithm (FEMA) that makes whole-brain vertex-wise, voxel-wise, and connectome-wide LME analyses in large samples possible. We validate FEMA with extensive simulations, showing that the estimates of the fixed effects are equivalent to standard maximum likelihood estimates but obtained with orders of magnitude improvement in computational speed. We demonstrate the applicability of FEMA by studying the cross-sectional and longitudinal effects of age on region-of-interest level and vertex-wise cortical thickness, as well as connectome-wide functional connectivity values derived from resting state functional MRI, using longitudinal imaging data from the Adolescent Brain Cognitive DevelopmentSM Study release 4.0. Our analyses reveal distinct spatial patterns for the annualized changes in vertex-wise cortical thickness and connectome-wide connectivity values in early adolescence, highlighting a critical time of brain maturation. The simulations and application to real data show that FEMA enables advanced investigation of the relationships between large numbers of neuroimaging metrics and variables of interest while considering complex study designs, including repeated measures and family structures, in a fast and efficient manner. The source code for FEMA is available via: https://github.com/cmig-research-group/cmig_tools/.

Associations Between Family History of Alcohol and/or Substance Use Problems and Frontal Cortical Development From 9 to 13 Years of Age: A Longitudinal Analysis of the ABCD Study.

Background: Previous investigations that have examined associations between family history (FH) of alcohol/substance use and adolescent brain development have been primarily cross-sectional. Here, leveraging a large population-based sample of youths, we characterized frontal cortical trajectories among 9- to 13-year-olds with (FH+) versus without (FH-) an FH and examined sex as a potential moderator. Methods: We used data from 9710 participants in the Adolescent Brain Cognitive Development (ABCD) Study (release 4.0). FH+ was defined as having ≥1 biological parents and/or ≥2 biological grandparents with a history of alcohol/substance use problems (n = 2433). Our primary outcome was frontal cortical structural measures obtained at baseline (ages 9-11) and year 2 follow-up (ages 11-13). We used linear mixed-effects models to examine the extent to which FH status qualified frontal cortical development over the age span studied. Finally, we ran additional interactions with sex to test whether observed associations between FH and cortical development differed significantly between sexes. Results: For FH+ (vs. FH-) youths, we observed increased cortical thinning from 9 to 13 years across the frontal cortex as a whole. When we probed for sex differences, we observed significant declines in frontal cortical thickness among boys but not girls from ages 9 to 13 years. No associations were observed between FH and frontal cortical surface area or volume. Conclusions: Having a FH+ is associated with more rapid thinning of the frontal cortex across ages 9 to 13, with this effect driven primarily by male participants. Future studies will need to test whether the observed pattern of accelerated thinning predicts future substance use outcomes.

Familial factors rather than paternal age contribute to the aetiology of epilepsy.

BACKGROUND: Whether paternal age associated with offspring's epilepsy risk is a cause of de novo mutation as men age, or just an association due to confounding factors, is still unclear. METHODS: We performed a population-based, multi-generation and sibling comparison study in Taiwan, which included 2 751 232 singletons born in 2001-17 who were followed until 2020. Of these, 819 371/826 087 with information on paternal/maternal grandparents were selected for multi-generation analyses and 1 748 382 with sibling(s) were selected for sibling comparison. Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: In the total cohort, there was an increased risk of epilepsy in individuals with advanced paternal age, e.g. the HR for paternal age ≥50 was1.36 (95% CI: 1.15-1.61) compared with paternal age 25-29, and fathers older than mothers, e.g. the HR for parental age difference ≥15 years was 1.29 (95% CI: 1.16-1.43). When accounting for parental age difference, the association between paternal age and epilepsy in offspring was attenuated (HR for paternal age ≥50 was 1.11, 95% CI: 0.93-1.34). Multi-generation analyses did not support the association of advanced grand-paternal age at childbirth of the parent with offspring's risk of epilepsy. Sibling comparison analyses did not support the association of older paternal age with increased risk of epilepsy (HR was 0.96 for per year increase in paternal age, 95% CI: 0.96-0.97). CONCLUSIONS: These results do not support the hypothesis that advanced paternal age is associated with epilepsy in offspring. Instead, familial factors may explain the observed paternal age association with the offspring's risk of epilepsy.

Brain structural covariance network features are robust markers of early heavy alcohol use.

BACKGROUND AND AIMS: Recently, we demonstrated that a distinct pattern of structural covariance networks (SCN) from magnetic resonance imaging (MRI)-derived measurements of brain cortical thickness characterized young adults with alcohol use disorder (AUD) and predicted current and future problematic drinking in adolescents relative to controls. Here, we establish the robustness and value of SCN for identifying heavy alcohol users in three additional independent studies. DESIGN AND SETTING: Cross-sectional and longitudinal studies using data from the Pediatric Imaging, Neurocognition and Genetics (PING) study (n = 400, age range = 14-22 years), the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) (n = 272, age range = 17-22 years) and the Human Connectome Project (HCP) (n = 375, age range = 22-37 years). CASES: Cases were defined based on heavy alcohol use patterns or former alcohol use disorder (AUD) diagnoses: 50, 68 and 61 cases were identified. Controls had none or low alcohol use or absence of AUD: 350, 204 and 314 controls were selected. MEASUREMENTS: Graph theory metrics of segregation and integration were used to summarize SCN. FINDINGS: Mirroring our prior findings, and across the three data sets, cases had a lower clustering coefficient [area under the curve (AUC) = -0.029, P = 0.002], lower modularity (AUC = -0.14, P = 0.004), lower average shortest path length (AUC = -0.078, P = 0.017) and higher global efficiency (AUC = 0.007, P = 0.010). Local efficiency differences were marginal (AUC = -0.017, P = 0.052). That is, cases exhibited lower network segregation and higher integration, suggesting that adjacent nodes (i.e. brain regions) were less similar in thickness whereas spatially distant nodes were more similar. CONCLUSION: Structural covariance network (SCN) differences in the brain appear to constitute an early marker of heavy alcohol use in three new data sets and, more generally, demonstrate the utility of SCN-derived metrics to detect brain-related psychopathology.

Effects of parental mental health and family environment on impulsivity in preadolescents: a longitudinal ABCD study®.

Introduction: Impulsivity is a known risk factor for the development of substance use disorders and other psychiatric conditions that is influenced by both genetics and environment. Although research has linked parental mental health to children's impulsivity, potential mediators of this relationship remain understudied. The current investigation leverages the large national Adolescent Brain Cognitive Development (ABCD) Study to assess the mediating role of family conflict - an important social context for youth development - in the relationship between parental mental health and youth impulsivity. Methods: Data were from the first three annual waves of the ABCD study (Baseline N = 11,876 children, Mage = 9.9 years; 48% female; 52% White). Parental mental health conditions were self-reported internalizing, externalizing, and total problems. Youth completed the family conflict scale, and Urgency, Planning (lack of), Perseverance (lack of), Sensation Seeking, and Positive Urgency (UPPS-P) scale to measure impulsivity. To determine if within-family change in conflict from baseline to year 1 explained changes in the strength of relations between baseline parental mental health and year 2 youth impulsivity, longitudinal causal mediation analyses were conducted, controlling for demographic factors (i.e., age, sex, race, household income, parental education, marital status), as well as baseline levels of family conflict and outcomes. Separate mediation models were run for each mental health condition and each UPPS-P subscale. Results: Above and beyond bivariate relations, longitudinal mediation models, which included covariates, showed family conflict significantly (ps < 0.001) mediated relations between all three parental mental health conditions and all but one (i.e., sensation seeking) UPPS-P subscales. The proportion mediated through family conflict for internalizing problems and total problems on facets of impulsivity (except sensation seeking) ranged from 9% (for lack of perseverance) to 17% (for lack of planning). Proportion mediated via family conflict for externalizing problems on youth's impulsivity (except sensation seeking) was slightly higher, ranging between 13% (lack of perseverance) to 21% (lack of planning). Discussion: Family conflict may be an important intergenerational factor linking parental mental health and youth's impulsivity. Addressing parental mental health and family conflict may help curb increased impulsivity in youth, and in turn reduce adolescent substance use disorders.

Population-based Risk of Psychiatric Disorders Associated with Recurrent CNVs.

Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We provide population-based estimates of rCNV-associated risk of neuropsychiatric disorders for 34 rCNVs in the iPSYCH2015 case-cohort sample (n=120,247). Most observed significant increases in rCNV-associated risk for ADHD, autism or schizophrenia were moderate (HR:1.42-5.00), and risk estimates were highly correlated across these disorders, the most notable exception being high autism-associated risk with Prader-Willi/Angelman Syndrome duplications (HR=20.8). No rCNV was associated with significant increase in depression risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint. Comparison with published rCNV studies suggests that prevalence of some rCNVs is higher, and risk of psychiatric disorders lower, than previously estimated. In an era where genetics is increasingly being clinically applied, our results highlight the importance of population-based risk estimates for genetics-based predictions.

Polygenic risk for neuroticism is associated with less efficient control in more difficult situations.

Neuroticism is a heritable trait and a risk factor for mental health due to its relevance to poor control of negative events. To examine the relationship between genetic propensity for neuroticism and control processing, we used the polygenic risk score (PRS) approach and a stop signal task during fMRI. We hypothesized that genetic propensity for neuroticism may moderate control processing as a function of control difficulty. PRSs for neuroticism were computed from a transdiagnostic group of individuals (n=406) who completed the stop signal task. The level of control difficulty was a function of the stop signal asynchrony: shorter asynchrony allows easier stopping whereas longer asynchrony makes stopping difficult. The relationship between PRS for neuroticism and neural activity for controlling responses was examined by the stop signal asynchrony. Although PRS for neuroticism did not relate to the overall inhibitory control, individuals with high PRS for neuroticism showed greater activity in left dorsal prefrontal cortex, middle temporal gyrus, and dorsal posterior cingulate cortex for difficult control. Thus, the genetic propensity for neuroticism affects neural processing in a difficult control context, which may help to explain why individuals with high levels of neuroticism exert poor control of negative events in difficult situations.

Associations between alcohol use and sex-specific maturation of subcortical gray matter morphometry from adolescence to adulthood: Replication across two longitudinal samples.

Subcortical brain morphometry matures across adolescence and young adulthood, a time when many youth engage in escalating levels of alcohol use. Initial cross-sectional studies have shown alcohol use is associated with altered subcortical morphometry. However, longitudinal evidence of sex-specific neuromaturation and associations with alcohol use remains limited. This project used generalized additive mixed models to examine sex-specific development of subcortical volumes and associations with recent alcohol use, using 7 longitudinal waves (n = 804, 51% female, ages 12-21 at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). A second, independent, longitudinal dataset, with up to four waves of data (n = 467, 43% female, ages 10-18 at baseline), was used to assess replicability. Significant, replicable non-linear normative volumetric changes with age were evident in the caudate, putamen, thalamus, pallidum, amygdala and hippocampus. Significant, replicable negative associations between subcortical volume and alcohol use were found in the hippocampus in all youth, and the caudate and thalamus in female but not male youth, with significant interactions present in the caudate, thalamus and putamen. Findings suggest a structural vulnerability to alcohol use, or a predisposition to drink alcohol based on brain structure, with female youth potentially showing heightened risk, compared to male youth.

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

INTRODUCTION: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19. METHODS: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14. RESULTS: Between 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19. CONCLUSION: De novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19. TRIAL REGISTRATION: Clinicaltrials.gov NCT04366050.

Estimating the Total Variance Explained by Whole-Brain Imaging for Zero-inflated Outcomes.

Zero-inflated outcomes are very common in behavioral data, particularly for responses to psychological questionnaires. Modeling these challenging distributions is further exacerbated by the absence of established statistical models capable of characterizing total signals attributed to whole-brain imaging features, making the accurate assessment of brain-behavior relationships particularly formidable. Given this critical need, we have developed a novel variational Bayes algorithm that characterizes the total signal captured by whole-brain imaging features for zero-inflated outcomes . Our zero-inflated variance (ZIV) estimator robustly estimates the fraction of variance explained (FVE) and the proportion of non-null effects from large-scale imaging data. In simulations, ZIV outperformed other linear prediction algorithms. Applying ZIV to data from one of the largest neuroimaging studies, the Adolescent Brain Cognitive Development SM (ABCD) Study, we found that whole-brain imaging features have a larger FVE for externalizing compared to internalizing behavior. We also demonstrate that the ZIV estimator, especially applied to focal sub-scales, can localize key neurocircuitry associated with human behavior.

A randomized controlled safety and feasibility trial of floatation-REST in anxious and depressed individuals.

Background: Reduced Environmental Stimulation Therapy via floatation (floatation-REST) is a behavioral intervention designed to attenuate exteroceptive sensory input to the nervous system. Pilot studies in anxious and depressed individuals demonstrated that single sessions of floatation-REST are safe, well-tolerated, and associated with acute anxiolysis. However, there is not sufficient evidence of the feasibility of floatation-REST as a repeated intervention. Methods: We randomized 75 individuals with anxiety and depression to six sessions of floatation-REST in different formats (pool-REST or pool-REST preferred) or an active comparator (chair-REST). Feasibility was assessed via adherence rate to the assigned intervention, tolerability via duration of REST utilization and overall study dropout rate, and safety via incidence of serious or non-serious adverse events. Results: Six-session adherence was 85% for pool-REST, 89% for pool-REST preferred, and 74% for chair-REST. Dropout rates did not differ significantly between the treatment conditions. Mean session durations were consistently above 50 minutes, and when allowed to choose the duration and frequency, participants opted to float for an average of 75 minutes. There were no serious adverse events associated with any intervention. Positive experiences were endorsed more commonly than negative ones and were also rated at higher levels of intensity. Conclusions: Taken together, six sessions of floatation-REST appear feasible, well-tolerated, and safe in anxious and depressed individuals. Floatation-REST induces positively-valenced experiences with few negative effects. Larger randomized controlled trials evaluating markers of clinical efficacy are warranted.Clinical Trial Registration Identifier: NCT03899090.

Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility.

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.

Intelligence Polygenic Score Is More Predictive of Crystallized Measures: Evidence From the Adolescent Brain Cognitive Development (ABCD) Study.

Findings in adults have shown that crystallized measures of intelligence, which are more culturally sensitive than fluid intelligence measures, have greater heritability; however, these results have not been found in children. The present study used data from 8,518 participants between 9 and 11 years old from the Adolescent Brain Cognitive Development (ABCD) Study. We found that polygenic predictors of intelligence test performance (based on genome-wide association meta-analyses of data from 269,867 individuals) and of educational attainment (based on data from 1.1 million individuals) predicted neurocognitive performance. We found that crystallized measures were more strongly associated with both polygenic predictors than were fluid measures. This mirrored heritability differences reported previously in adults and suggests similar associations in children. This may be consistent with a prominent role of gene-environment correlation in cognitive development measured by crystallized intelligence tests. Environmental and experiential mediators may represent malleable targets for improving cognitive outcomes.

Prospective associations between cannabis use and depressive symptoms across adolescence and early adulthood.

Cannabis use and occurrences of depression during adolescence are common. However, the temporal relationship between the two is less understood. Does depression lead to cannabis use, or does cannabis use lead to depression, or is it a combination of both? Furthermore, this directionality is confounded by other substance use, specifically binge drinking, which is common during adolescence. This study aimed to examine the temporal directionality of cannabis use and depression among a prospective, longitudinal, sequential cohort of 15 to 24-year-olds. Data were drawn from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. The final sample included 767 participants. Multilevel regression models were run to assess concurrent (at the same time point) and prospective (1 year later) associations between cannabis use and depression. When measured concurrently, depressive symptoms did not significantly predict past-month cannabis use but did significantly predict more days of use among cannabis users. Prospective associations indicated that depressive symptoms significantly predicted cannabis use 1 year later and cannabis use significantly predicted depressive symptoms 1 year later. We found no evidence that these associations varied by age or binge drinking. Overall, the relationship between cannabis use and depression appears to be complex and not unidirectional.

Pandemic-Related Changes in the Prevalence of Early Adolescent Alcohol and Drug Use, 2020-2021: Data From a Multisite Cohort Study.

PURPOSE: Evaluate changes in early adolescent substance use from May 2020 to May 2021 during the coronavirus disease 2019 pandemic using data from a prospective nationwide cohort: the Adolescent Brain Cognitive Development Study. METHODS: In 2018-2019, 9,270 youth aged 11.5-13.0 completed a prepandemic assessment of past-month alcohol and drug use, then up to seven during-pandemic assessments between May 2020 and May 2021. We compared the prevalence of substance use among same-age youth across these eight timepoints. RESULTS: Pandemic-related decreases in the past-month prevalence of alcohol use were detectable in May 2020, grew larger over time, and remained substantial in May 2021 (0.3% vs. 3.2% prepandemic, p <.001). Pandemic-related increases in inhalant use (p = .04) and prescription drug misuse (p < .001) were detectable in May 2020, shrunk over time, and were smaller but still detectable in May 2021(0.1%-0.2% vs. 0% pre-pandemic). Pandemic-related increases in nicotine use were detectable between May 2020 and March 2021 and no longer significantly different from prepandemic levels in May 2021 (0.5% vs. 0.2% prepandemic, p = .09). There was significant heterogeneity in pandemic-related change in substance use at some timepoints, with increased rates among youth identified as Black or Hispanic or in lower-income families versus stable or decreased rates among youth identified as White or in higher-income families. DISCUSSION: Among youth ages 11.5-13.0 years old, rates of alcohol use remained dramatically reduced in May 2021 relative to prepandemic and rates of prescription drug misuse and inhalant use remained modestly increased. Differences remained despite the partial restoration of prepandemic life, raising questions about whether youth who spent early adolescence under pandemic conditions may exhibit persistently different patterns of substance use.

Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Heritability Estimation of Cognitive Phenotypes in the ABCD Study® Using Mixed Models.

Twin and family studies have historically aimed to partition phenotypic variance into components corresponding to additive genetic effects (A), common environment (C), and unique environment (E). Here we present the ACE Model and several extensions in the Adolescent Brain Cognitive Development℠ Study (ABCD Study®), employed using the new Fast Efficient Mixed Effects Analysis (FEMA) package. In the twin sub-sample (n = 924; 462 twin pairs), heritability estimates were similar to those reported by prior studies for height (twin heritability = 0.86) and cognition (twin heritability between 0.00 and 0.61), respectively. Incorporating SNP-derived genetic relatedness and using the full ABCD Study® sample (n = 9,742) led to narrower confidence intervals for all parameter estimates. By leveraging the sparse clustering method used by FEMA to handle genetic relatedness only for participants within families, we were able to take advantage of the diverse distribution of genetic relatedness within the ABCD Study® sample.