RESUMO
Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.
Assuntos
Alcoolismo , Estudo de Associação Genômica Ampla , Adulto , Adolescente , Criança , Humanos , Recém-Nascido , Estudos Longitudinais , Alcoolismo/genética , Consumo de Bebidas Alcoólicas/genética , Estudos de CoortesRESUMO
We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (ßindirect = -0.018 [-0.026, -0.011]) and intoxication (ßindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (ßindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (ßindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.
Assuntos
Transtornos Relacionados ao Uso de Álcool , Intoxicação Alcoólica , Alcoolismo , Criança , Adolescente , Humanos , Feminino , Masculino , Alcoolismo/genética , Consumo de Bebidas Alcoólicas , Fatores de RiscoRESUMO
In this study, we test principal component analysis (PCA) of measured confounders as a method to reduce collider bias in polygenic association models. We present results from simulations and application of the method in the Collaborative Study of the Genetics of Alcoholism (COGA) sample with a polygenic score for alcohol problems, DSM-5 alcohol use disorder as the target phenotype, and two collider variables: tobacco use and educational attainment. Simulation results suggest that assumptions regarding the correlation structure and availability of measured confounders are complementary, such that meeting one assumption relaxes the other. Application of the method in COGA shows that PC covariates reduce collider bias when tobacco use is used as the collider variable. Application of this method may improve PRS effect size estimation in some cases by reducing the effect of collider bias, making efficient use of data resources that are available in many studies.
Assuntos
Alcoolismo , Herança Multifatorial , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Viés , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Análise de Componente PrincipalRESUMO
Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.
Assuntos
Moléculas de Adesão Celular/genética , Assunção de Riscos , Autocontrole , Comportamento Sexual , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Consumo de Bebidas Alcoólicas/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Países Baixos , Polimorfismo de Nucleotídeo Único , Fumar/genética , Fatores SociodemográficosRESUMO
OBJECTIVE: In the current exploratory study we estimate comorbidity rates between FDs [fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and irritable bowel syndrome (IBS)]-and IDs-[major depressive disorder (MDD) and generalized anxiety disorder (GAD)] by using self-reported diagnostic criteria. METHOD: We analyzed data from 107,849 participants (mean age = 49.3 (SD = 13.0), 58.6% women) of the Lifelines Cohort Study. Lifelines is a prospective population-based cohort study in the northeast of the Netherlands. Current IDs were assessed using the Mini-International Neuropsychiatric Interview. Current FM, ME/CFS, and IBS were assessed according to the 2010 American College of Rheumatology criteria, the 1994 Centers for Disease Control and Prevention criteria and the ROME IV criteria, respectively. We estimated tetrachoric correlations between diagnoses and tested for sex differences. Additionally, we estimated the ratio of observed-to-expected frequency for combinations of diagnoses. RESULTS: FDs and IDs are highly comorbid (odds ratios: 3.2-12.6) with associations stronger among men. Participants with at least three disorders/diagnoses were more prevalent than expected by chance. CONCLUSION: Studies that aim to explain sex differences and the comorbidity of specific combinations of IDs and FDs will be an important contribution to understanding the etiology of these conditions.
RESUMO
BACKGROUND: Parental divorce and discord are associated with poorer alcohol-related outcomes for offspring. However, not all children exposed to these stressors develop alcohol problems. Our objective was to test gene-by-environment interaction effects whereby children's genetic risk for alcohol problems modifies the effects of parental divorce and discord to predict alcohol outcomes. METHODS: The sample included European (EA; N = 5608, 47% male, Mage ~ 36 years) and African (AA; N = 1714, 46% female, Mage ~ 33 years) ancestry participants from the Collaborative Study on the Genetics of Alcoholism. Outcomes included age at initiation of regular drinking and lifetime DSM-5 alcohol use disorder (AUD). Predictors included parental divorce, parental relationship discord, and offspring alcohol problems polygenic risk scores (PRSALC ). Mixed effects Cox proportional hazard models were used to examine alcohol initiation and generalized linear mixed effects models were used to examine lifetime AUD. Tests of PRS moderation of the effects of parental divorce/relationship discord on alcohol outcomes were examined on multiplicative and additive scales. RESULTS: Among EA participants, parental divorce, parental discord, and higher PRSALC were associated with earlier alcohol initiation and greater lifetime AUD risk. Among AA participants, parental divorce was associated with earlier alcohol initiation and discord was associated with earlier initiation and AUD. PRSALC was not associated with either. Parental divorce/discord and PRSALC interacted on an additive scale in the EA sample, but no interactions were found in AA participants. CONCLUSIONS: Children's genetic risk for alcohol problems modifies the impact of parental divorce/discord, consistent with an additive model of diathesis-stress interaction, with some differences across ancestry.
Assuntos
Transtornos Relacionados ao Uso de Álcool , Alcoolismo , Humanos , Masculino , Criança , Feminino , Adulto , Alcoolismo/epidemiologia , Alcoolismo/genética , Divórcio , Pais , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genéticaRESUMO
OBJECTIVE: To examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample. METHOD: Participants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage â¼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit. RESULTS: Among EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce. CONCLUSIONS: In a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Assuntos
Transtornos Relacionados ao Uso de Álcool , Alcoolismo , Transtorno Depressivo Maior , Abuso de Maconha , Adulto , Transtornos Relacionados ao Uso de Álcool/psicologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Alcoolismo/psicologia , Transtorno Depressivo Maior/epidemiologia , Divórcio/psicologia , Feminino , Humanos , Masculino , CasamentoRESUMO
BACKGROUND: Among adult college students in the US, cannabis use is common and associated with considerable negative consequences to health, cognition, and academic functioning, underscoring the importance of identifying risk and protective factors. Cannabis use is influenced by genetic factors, but genetic risk is not determinative. Accordingly, it is critical to identify environments that reduce risk among those who are at elevated genetic risk. This study examined the impact of polygenic scores for cannabis initiation, various forms of social activity participation, and peer deviance on recent cannabis use. Our aim was to test whether these environments moderate genetic risk for cannabis use. METHODS: Data came from a longitudinal sample of undergraduate college students of European American (EA; NEA = 750) and African American (AA; NAA = 405) ancestry. Generalized estimating equations with a logit link function were used to examine main effects and two-way interactions. RESULTS: Engagement with church activities was associated with lower probability of cannabis use. Peer deviance was associated with higher probability of cannabis use. Engagement with community activities moderated the influence of the polygenic risk score in the EA sample, such that PRS was associated with recent cannabis use among those who never engaged in community activities. This effect did not replicate in AAs, which may have been due to the portability of PRS based on EA discovery samples. CONCLUSIONS: Results suggest that community activities may limit the influence of genetic risk, as associations between PRS and cannabis use were only observed among individuals who never engaged in community activities.
Assuntos
Cannabis , Fumar Maconha/epidemiologia , Universidades , Adolescente , Adulto , Negro ou Afro-Americano/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial , Grupo Associado , Fatores de Risco , Estudantes , Transtornos Relacionados ao Uso de Substâncias , População Branca/genéticaRESUMO
E-cigarettes have dramatically increased in popularity among youth. Coincident with expanded legalization, young adults' use of cannabis (marijuana) has also steadily increased in recent years. Use of tobacco products can increase the chances of later cannabis initiation among youth. However, most longitudinal investigations of tobacco and cannabis use patterns have focused on tobacco cigarettes, included adolescents as opposed to young adults, and have only employed two timepoints. The current study examined prospective associations between e-cigarette and cannabis use in a large, diverse college sample assessed over four timepoints (freshman - senior year; N = 4,670). E-cigarette use and cannabis use were modelled in a four-wave cross-lagged model. The results showed significant bidirectional associations between both substances, even after controlling for time-varying levels of depressive symptoms, alcohol use, and polysubstance use, sensation seeking, demographic variables, concurrent associations and previous levels of use. Moreover, the significance of the predictive path from e-cigarette use to later cannabis use remained unchanged when we ran the same model, but restricted the sample to e-cigarette-only users (i.e., never cigarette smokers), whereas only one prospective path from cannabis to e-cigarette use was significant in this subsample. The current findings suggest that the association of e-cigarette use and cannabis use is likely bidirectional, with stronger support for the link from e-cigarette use to later cannabis use, above and beyond cigarette use. As e-cigarettes gain further hold of the tobacco product market share and cannabis legalization continues to expand, data such as these will be critical for informing regulatory decisions for e-cigarettes and cannabis, particularly involving their accessibility to youth and young adults.
Assuntos
Cannabis , Sistemas Eletrônicos de Liberação de Nicotina , Vaping , Adolescente , Humanos , Estudos Prospectivos , Estudantes , Adulto JovemRESUMO
OBJECTIVE: Evidence suggests that the nature and magnitude of some genetic effects on alcohol use vary by age. We tested for moderation in the effect of an alcohol metabolizing polygenic score by time across the college years. METHOD: Participants (total n = 2,214) were drawn from three cohorts of undergraduate college students, who were assessed annually for up to 4 years starting in their freshman year. Polygenic risk scores (PRSs) were calculated from genes involved in the metabolism of alcohol, as many of these markers are among the best replicated in association studies examining alcohol use phenotypes. Linear mixed effects models were fit by maximum likelihood to test the main effects of time and the PRS on alcohol consumption, as well as moderation of the PRS effect on alcohol consumption by time. RESULTS: In the main effects model, the fixed effects for time and the PRS were positively associated with alcohol consumption. The interaction term testing moderation of the PRS effect by time reached statistical significance and remained statistically significant after other relevant interaction effects were controlled for. The main effect of the PRS accounted for 0.2% of the variance in alcohol consumption, whereas the interaction of PRS effect and time accounted for 0.05%. CONCLUSIONS: Alcohol metabolizing genetic effects on alcohol use appear to be more influential in later years of college than in earlier years. Shifting environmental contexts, such as increased access to alcohol as individuals approach the legal age to purchase alcohol, may account for this association.
Assuntos
Consumo de Álcool na Faculdade/psicologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Herança Multifatorial/genética , Estudantes/psicologia , População Branca/genética , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Estados Unidos/epidemiologia , Universidades/tendências , Adulto JovemRESUMO
Dating several people in emerging adulthood has been associated with higher alcohol use compared with being single or being in an exclusive relationship. As a follow-up to that report, we examined whether romantic relationship status is part of a pathway of risk between antecedent alcohol use risk factors and subsequent alcohol outcomes. Participants were 4,410 emerging adults assessed at 2 time-points during their first year of college. We found that a parental history of alcohol problems was indirectly related to dating several people via 2 modestly correlated pathways. The first pathway was through conduct problems. The second pathway was through positive urgency (i.e., a positive emotion-based predisposition to rash action). In turn, dating several people was associated with higher alcohol use. Our results suggest that these familial and individual-level alcohol risk factors are related to emerging adults' selection into subsequent romantic relationship experiences that are associated with higher alcohol use. These findings have implications for how romantic relationship experiences may fit into developmental models of the etiology of alcohol use. (PsycINFO Database Record