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Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood.

ABSTRACT: Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18-31 (beta coefficients ranged from 0.02-0.06, p-values ranged from 10^-6-10^-12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective.

SUBMITTER: Meyers JL

PROVIDER: S-EPMC6826735 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood.

Meyers Jacquelyn L JL Chorlian David B DB Johnson Emma C EC Pandey Ashwini K AK Kamarajan Chella C Salvatore Jessica E JE Aliev Fazil F Subbie-Saenz de Viteri Stacey S Zhang Jian J Chao Michael M Kapoor Manav M Hesselbrock Victor V Kramer John J Kuperman Samuel S Nurnberger John J Tischfield Jay J Goate Alison A Foroud Tatiana T Dick Danielle M DM Edenberg Howard J HJ Agrawal Arpana A Porjesz Bernice B

Brain sciences 20191017 10

Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity ( ...[more]

PMID: 31627376

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Project description:BackgroundThe role of alcohol use in the development of depression is unclear. We aimed to investigate whether alcohol dependence, but not high frequency or quantity of consumption, during adolescence increased the risk of depression in young adulthood.MethodsIn this prospective cohort study, we included adolescents who were born to women recruited to the Avon Longitudinal Study of Parents and Children in Avon, UK, with delivery dates between April 1, 1991, and Dec 31, 1992. Alcohol dependence and consumption were measured at about age 16 years, 18 years, 19 years, 21 years, and 23 years using the self-reported Alcohol Use Disorders Identification Test, and at about age 18 years, 21 years, and 23 years using items corresponding to DSM-IV symptoms. The primary outcome was depression at age 24 years, assessed using the Clinical Interview Schedule Revised. Analyses were probit regressions between growth factors for alcohol dependence and consumption and depression, before and after adjustments for confounders: sex, housing tenure, maternal education, maternal depressive symptoms, parents' alcohol use, conduct problems at age 4 years, being bullied from age 12-16 years, and frequency of smoking cigarettes or cannabis. Adolescents were included in analyses if they had data from at least one timepoint for alcohol use and confounders.FindingsWe included 3902 adolescents (2264 [58·0%] female; 1638 [42·0%] male) in our analysis, and 3727 (96·7%) of 3853 participants with data on ethnicity were White. After adjustments, we found a positive association between alcohol dependence at 18 years of age (latent intercept) and depression at 24 years of age (probit coefficient 0·13 [95% CI 0·02 to 0·25]; p=0·019), but no association between rate of change (linear slope) and depression (0·10 [-0·82 to 1·01]; p=0·84). There was no evidence of an association between alcohol consumption and depression (latent intercept probit coefficient -0·01 [-0·06 to 0·03]; p=0·60; linear slope 0·01 [-0·40 to 0·42]; p=0·96) after adjustments.InterpretationPsychosocial or behavioural interventions that reduce the risk of alcohol dependence during adolescence could contribute to preventing depression in young adulthood.FundingUK Medical Research Council and Alcohol Research UK (grant number MR/L022206/1).

Project description:Background and aimsMolecular 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 measurementsWe 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.FindingsEach PGS was associated with trajectories of use for their respective substances [i.e. DPW (βmean = 0.08; βrange = 0.02-0.12) and PAU (βmean = 0.12; βrange = -0.02 to 0.31) for alcohol; CPD (βmean = 0.08; βrange = 0.04-0.14) and SMK (βmean = 0.18; βrange = 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 (βmean = 0.15; βrange = 0.02-0.33), even after adjusting for the respective effects of all other PGSs.ConclusionsSubstance 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.

Project description:BackgroundExternalizing behavior has been attributed, in part, to decreased frontolimbic control over amygdala activation. However, little is known about developmental trajectories of frontoamygdalar functional connectivity and its relation to externalizing behavior. The present study addresses this gap by examining longitudinal associations between adolescent and adult externalizing behavior and amygdala-anterior cingulate cortex (ACC) and amygdala-orbitofrontal cortex (OFC) resting-state functional connectivity in a sample of 111 typically developing participants aged 11-23 at baseline.MethodsParticipants completed two-to-four data waves spaced approximately two years apart, resulting in a total of 309 data points. At each data wave, externalizing behavior was measured using the Externalizing Behavior Broadband Scale from the Achenbach Youth/Adult Self-Report questionnaire. Resting-state fMRI preprocessing was performed using FSL. Amygdala functional connectivity was examined using AFNI. The longitudinal association between externalizing behavior and amygdala-ACC/OFC functional connectivity was examined using linear mixed effect models in R.ResultsExternalizing behavior was associated with increased amygdala-ACC and amygdala-OFC resting-state functional connectivity across adolescence and young adulthood. For amygdala-ACC connectivity, externalizing behavior at baseline primarily drove this association, whereas for amygdala-OFC functional connectivity, change in externalizing behavior relative to baseline drove the main effect of externalizing behavior on amygdala-OFC functional connectivity. No evidence was found for differential developmental trajectories of frontoamygdalar connectivity for different levels of externalizing behavior (i.e., age-by-externalizing behavior interaction effect).ConclusionsHigher externalizing behavior is associated with increased resting-state attunement between the amygdala and ACC/OFC, perhaps indicating a generally more vigilant state for neural networks important for emotional processing and control.

Project description:Co-twin comparisons address familial confounding by controlling for genetic and environmental influences that twin siblings share. We applied the co-twin comparison design to investigate associations of adolescent factors with alcohol dependence (AD) symptoms. Participants were 1286 individuals (581 complete twin pairs; 42% monozygotic; and 54% female) from the FinnTwin12 study. Predictors included adolescent academic achievement, substance use, externalizing problems, internalizing problems, executive functioning, peer environment, physical health, relationship with parents, alcohol expectancies, life events, and pubertal development. The outcome was lifetime AD clinical criterion count, as measured in young adulthood. We examined associations of each adolescent domain with AD symptoms in individual-level and co-twin comparison analyses. In individual-level analyses, adolescents with higher levels of substance use, teacher-reported externalizing problems at age 12, externalizing problems at age 14, self- and co-twin-reported internalizing problems, peer deviance, and perceived difficulty of life events reported more symptoms of AD in young adulthood (ps < .044). Conversely, individuals with higher academic achievement, social adjustment, self-rated health, and parent-child relationship quality met fewer AD clinical criteria (ps < .024). Associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, self-rated health, and AD symptoms were of a similar magnitude in co-twin comparisons. We replicated many well-known adolescent correlates of later alcohol problems, including academic achievement, substance use, externalizing and internalizing problems, self-rated health, and features of the peer environment and parent-child relationship. Furthermore, we demonstrate the utility of co-twin comparisons for understanding pathways to AD. Effect sizes corresponding to the associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, and self-rated health were not significantly attenuated (p value threshold = .05) after controlling for genetic and environmental influences that twin siblings share, highlighting these factors as candidates for further research.

Project description:ImportanceDepressive symptoms have increased among US adolescents since 2010. It remains unclear as to what extent this increase will persist into young adulthood, potentially turning the youth mental health crisis into a young adult mental health crisis.ObjectiveTo test the association between birth cohort and adolescent depressive symptoms at ages 18, 19 to 20, and 21 to 22 years and changes in these symptoms by cohort.Design, setting, and participantsThis panel cohort study analyzed data from the Monitoring the Future longitudinal survey from 1990 to 2019, including birth cohorts from 1972 to 2001. Survey respondents were recruited from US high schools in 12th grade and were approximately aged 18 years (at baseline) through age 21 to 22 years (during mail and web follow-up). Data analysis was conducted from April to October 2023.ExposureDepressive symptoms score (>12 vs ≤12, with >12 representing top-decile scores) on a scale examining affective items (eg, "Life often seems meaningless").Main outcomes and measuresHigh (vs lower) depressive symptoms at ages 19 to 20 years and 21 to 22 years.ResultsThe 36 552 respondents included 18 597 females (50.5%), and most reported having a parent who graduated from college (44.8%). Among females, 19.1% (95% CI, 16.7%-21.4%) of the most recent birth cohort (born: 1997-2001) had high depressive symptoms at age 18 years, higher than any previous birth cohort. While prevalence declined by age 21 to 22 years, it remained higher than previous cohorts at that age. Among males, 13.4% (95% CI, 11.2%-15.6%) of the most recent birth cohort had high depressive symptoms at age 18 years, and prevalence increased through young adulthood. Males with high baseline depressive symptoms had 10.24 (95% CI, 7.01-14.97) times the odds of symptoms at age 19 to 20 years and 6.20 (95% CI, 3.93-9.78) times the odds of symptoms at age 21 to 22 years. Females with high baseline depressive symptoms had 9.16 (95% CI, 6.57-12.76) times the odds of symptoms at age 19 to 20 years and 7.28 (95% CI, 4.92-10.78) times the odds of symptoms at age 21 to 22 years. The magnitude of the associations did not vary over time. Population attributable fractions indicated that the total proportion of young adult symptoms associated with depressive symptoms at age 18 years among females has increased; in the most recent birth cohort, 55.25% (95% CI, 38.11%-65.13%) of depressive symptoms at age 21 to 22 years were associated with symptoms at age 18 years.Conclusions and relevanceThis panel cohort study found that increases in depressive symptoms in adolescence persisted into young adulthood, suggesting the need for primary prevention and mental health resources during the adolescent years.

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Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood.

Publications

Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood.

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