Predicting alcohol consumption in adolescence from alcohol-specific and general externalizing genetic risk factors, key environmental exposures and their interaction

BackgroundAlcohol consumption is influenced by specific genetic risk factors for alcohol use disorders (AUDs), non-specific genetic risk factors for externalizing behaviors and various environmental experiences. We have limited knowledge of how these risk factors inter-relate through development.MethodRetrospective assessments in 1796 adult male twins using a life history calendar of key environmental exposures and alcohol consumption from early adolescence to mid-adulthood. Analysis by linear mixed models.ResultsThe importance of non-specific genetic risk factors on maximal alcohol consumption rose rapidly in early to mid-adolescence, peaked at ages 15–17 years and then declined slowly. Alcohol-specific genetic risk factors increased slowly in influence through mid-adulthood. We detected robust evidence for environmental moderation of genetic effects on alcohol consumption that was more pronounced in early and mid-adolescence than in later periods. Alcohol availability, peer deviance and low prosocial behaviors showing the strongest moderation effects. More interactions with environmental risk factors were seen for the non-specific externalizing disorder risk than for specific genetic risk for AUDs.ConclusionsThe impact of specific and non-specific genetic influences on alcohol consumption have different development trajectories. Genetic effects on alcohol use are more pronounced when social constraints are minimized (e.g. low prosocial behaviors or parental monitoring) or when the environment permits easy access to alcohol and/or encourages its use (e.g. high alcohol availability or peer deviance). Gene–environment interactions influencing alcohol intake may be more robust at younger ages, indicating greater plasticity of genetic influences early in the development of drinking patterns.

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Chromatin architecture in addiction circuitry elucidates biological mechanisms underlying cigarette smoking and alcohol use traits.

10.1101/2021.03.18.436046 ◽

2021 ◽

Author(s):

Nancy Y.A Sey ◽

Benxia Hu ◽

Marina Iskhakova ◽

Huaigu Sun ◽

Neda Shokrian ◽

...

Keyword(s):

Risk Factors ◽

Alcohol Use ◽

Cigarette Smoking ◽

Genetic Risk ◽

Target Genes ◽

Association Studies ◽

Critical Role ◽

Genetic Risk Factors ◽

Genome Wide Association Studies ◽

Risk Genes

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ~26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture refines neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

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Common Genetic Risk of Major Depression and Nicotine Dependence: The Contribution of Antisocial Traits in a United States Veteran Male Twin Cohort

Twin Research and Human Genetics ◽

10.1375/twin.10.3.470 ◽

2007 ◽

Vol 10 (3) ◽

pp. 470-478 ◽

Cited By ~ 15

Author(s):

Qiang Fu ◽

Andrew C. Heath ◽

Kathleen K. Bucholz ◽

Michael J. Lyons ◽

Ming T. Tsuang ◽

...

Keyword(s):

Risk Factors ◽

Major Depression ◽

Predominantly White ◽

Nicotine Dependence ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Diagnostic Interview ◽

Genetic Influences ◽

Vietnam Era ◽

Shared Genetic

AbstractMany studies that found associations between depression and nicotine dependence have ignored possible shared genetic influences associated with antisocial traits. The present study examined the contribution of genetic and environmental effects associated with conduct disorder (CD) and antisocial personality disorder (ASPD) to the comorbidity of major depression (MD) and nicotine dependence (ND). A telephone diagnostic interview, the Diagnostic Interview Schedule-III-R, was administered to eligible twins from the Vietnam Era Twin (VET) Registry in 1992. Multivariate genetic models were fitted to 3360 middle-aged and predominantly white twin pairs (1868 monozygotic, 1492 dizygotic pairs) of which both members completed the pertinent diagnostic interview sections. Genetic influences on CD accounted for 100%, 68%, and 50% of the total genetic variance in risk for ASPD, MD and ND, respectively. After controlling for genetic influences on CD, the partial genetic correlation between MD and ND was no longer statistically significant. Nonshared environmental contributions to the comorbidity among these disorders were not significant. This study not only demonstrates that the comorbidity between ND and MD is influenced by common genetic risk factors, but also further suggests that the common genetic risk factors overlapped with those for antisocial traits such as CD and ASPD in men.

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SU138SHARING OF GENETIC RISK FACTORS BETWEEN DIFFERENT PROXY MEASURES OF ALCOHOL USE DISORDERS AND RISK OF MENTAL HEALTH DISORDERS

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2018.08.502 ◽

2019 ◽

Vol 29 ◽

pp. S1340

Author(s):

Andries Marees ◽

Dirk Smit ◽

Jue_Sheng Ong ◽

Stuart MacGregor ◽

Jiyuan An ◽

...

Keyword(s):

Mental Health ◽

Risk Factors ◽

Alcohol Use ◽

Genetic Risk ◽

Alcohol Use Disorders ◽

Genetic Risk Factors ◽

Mental Health Disorders ◽

Health Disorders

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Non-genetic risk factors for atrial fibrillation are equally important in both young and old age: A nationwide population-based study

European Journal of Preventive Cardiology ◽

10.1177/2047487320915664 ◽

2020 ◽

pp. 204748732091566

Author(s):

Yun Gi Kim ◽

Kyung-Do Han ◽

Jong-Il Choi ◽

Yun Young Choi ◽

Ha Young Choi ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Alcohol Consumption ◽

Genetic Risk ◽

Age Groups ◽

Genetic Risk Factors ◽

Population Based ◽

The Impact ◽

Onset Atrial Fibrillation ◽

New Onset

Aims There are several non-genetic risk factors for new-onset atrial fibrillation, including age, sex, obesity, hypertension, diabetes, and alcohol consumption. However, whether these non-genetic risk factors have equal significance among different age groups is not known. We performed a nationwide population-based analysis to compare the clinical significance of non-genetic risk factors for new-onset atrial fibrillation in various age groups. Methods and results A total of 9,797,409 people without a prior diagnosis of atrial fibrillation who underwent a national health check-up in 2009 were included. During 80,130,090 person-years of follow-up, a total of 196,136 people were diagnosed with new-onset atrial fibrillation. The impact of non-genetic risk factors on new-onset atrial fibrillation was examined in different age groups. Obesity, male sex, heavy alcohol consumption, smoking, hypertension, diabetes and chronic kidney disease were associated with an increased risk of new-onset atrial fibrillation. With minor variations, these risk factors were consistently associated with the risk of new-onset atrial fibrillation among various age groups. Using these risk factors, we created a scoring system to predict future risk of new-onset atrial fibrillation in different age groups. In receiver operating characteristic curve analysis, the predictive value of these risk factors ranged between 0.556 and 0.603, and no significant trends were observed. Conclusions Non-genetic risk factors for new-onset atrial fibrillation may have a similar impact on different age groups. Except for sex, these non-genetic risk factors can be modifiable. Therefore, efforts to control non-genetic risk factors might have relevance for both the young and old.

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A developmental model for alcohol use disorders in Swedish men

Psychological Medicine ◽

10.1017/s0033291716001409 ◽

2016 ◽

Vol 46 (13) ◽

pp. 2759-2770 ◽

Cited By ~ 7

Author(s):

K. S. Kendler ◽

H. Ohlsson ◽

A. C. Edwards ◽

J. Sundquist ◽

K. Sundquist

Keyword(s):

Risk Factors ◽

Alcohol Consumption ◽

Alcohol Use ◽

Genetic Risk ◽

Criminal Behavior ◽

Early Adulthood ◽

Model Fitting ◽

Developmental Model ◽

Best Fitting

BackgroundAlcohol use disorder (AUD) is a classic multifactorial syndrome and it is critical to understand the diversity of the relevant risk factors and how they inter-relate over development.MethodWe examined 21 risk factors for AUD in four developmental tiers reflecting (i) birth, (ii) childhood and early adolescence, (iii) late adolescence, and (iv) early adulthood in 47 414 Swedish men of whom 3907 (8.2%) were registered for AUD at or after age 25 with a mean length of follow-up of 33.9 (6.6) years. Structural equational model fitting was performed using Mplus.ResultsThe best-fitting model provided a good fit to the data and explained 23.4% of the variance in AUD. The five strongest predictors were: externalizing behaviors, criminal behavior, father's alcohol consumption, genetic risk, and low educational attainment. Two developmentally early familial/genetic risk factors had substantial direct paths to AUD: father's alcohol consumption and genetic liability. Other broad developmental pathways to risk for AUD were evident: externalizing, psychosocial and internalizing. Overall, the externalizing pathway to AUD was the strongest. However, these pathways were substantially interwoven over time such that risk factors from one domain were commonly predicted by and/or predicted risk factors from the other broad domains of risk.ConclusionAUD in men is an etiologically complex syndrome influenced by familial-genetic, psychosocial, internalizing, and especially externalizing risk factors that act and interact over development and have complicated mediational pathways.

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Genetic Regulation of Transcription in the Endometrium in Health and Disease

Frontiers in Reproductive Health ◽

10.3389/frph.2021.795464 ◽

2022 ◽

Vol 3 ◽

Author(s):

Sally Mortlock ◽

Brett McKinnon ◽

Grant W. Montgomery

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Genetic Variation ◽

Menstrual Cycle ◽

Gene Mapping ◽

Genetic Risk ◽

Genetic Regulation ◽

Regulation Of Gene Expression ◽

Genetic Risk Factors ◽

Genetic Effects

The endometrium is a complex and dynamic tissue essential for fertility and implicated in many reproductive disorders. The tissue consists of glandular epithelium and vascularised stroma and is unique because it is constantly shed and regrown with each menstrual cycle, generating up to 10 mm of new mucosa. Consequently, there are marked changes in cell composition and gene expression across the menstrual cycle. Recent evidence shows expression of many genes is influenced by genetic variation between individuals. We and others have reported evidence for genetic effects on hundreds of genes in endometrium. The genetic factors influencing endometrial gene expression are highly correlated with the genetic effects on expression in other reproductive (e.g., in uterus and ovary) and digestive tissues (e.g., salivary gland and stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. There is also increasing evidence for cell specific genetic effects for some genes. Sample size for studies in endometrium are modest and results from the larger studies of gene expression in blood report genetic effects for a much higher proportion of genes than currently reported for endometrium. There is also emerging evidence for the importance of genetic variation on RNA splicing. Gene mapping studies for common disease, including diseases associated with endometrium, show most variation maps to intergenic regulatory regions. It is likely that genetic risk factors for disease function through modifying the program of cell specific gene expression. The emerging evidence from our gene mapping studies coupled with tissue specific studies, and the GTEx, eQTLGen and EpiMap projects, show we need to expand our understanding of the complex regulation of gene expression. These data also help to link disease genetic risk factors to specific target genes. Combining our data on genetic regulation of gene expression in endometrium, and cell types within the endometrium with gene mapping data for endometriosis and related diseases is beginning to uncover the specific genes and pathways responsible for increased risk of these diseases.

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