Publications by authors named "Fazil Aliev"

91 Publications

Predicting Alcohol Dependence Symptoms by Young Adulthood: A Co-Twin Comparisons Study.

Twin Res Hum Genet 2021 Aug 16;24(4):204-216. Epub 2021 Sep 16.

Department of Psychology, Virginia Commonwealth University, Richmond, Virginia, USA.

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.
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http://dx.doi.org/10.1017/thg.2021.36DOI Listing
August 2021

The associations between polygenic risk, sensation seeking, social support, and alcohol use in adulthood.

J Abnorm Psychol 2021 Jul;130(5):525-536

Department of Psychology.

Genetic predispositions play an important role in alcohol use. Understanding the psychosocial mechanisms through which genetic risk unfolds to influence alcohol use outcomes is critical for identifying modifiable targets and developing prevention and intervention efforts. In this study, we examined the role of sensation seeking and social support from family and friends in linking genetic risk to alcohol use. We also examined the role of social support in moderating the associations between genetic risk and sensation seeking and alcohol use. Data were drawn from a sample of 2,836 European American adults from the Collaborative Study on the Genetics of Alcoholism (46% male, mean age = 35.65, standard deviation [] = 10.78). Results from path analysis indicated that genome-wide polygenic scores for alcohol consumption (alc-GPS) were associated with higher sensation seeking, which in turn was associated with higher levels of alcohol use. alc-GPS was also associated with higher alcohol use indirectly via lower levels of family support. In addition, high friend support attenuated the association between alc-GPS and sensation seeking and alcohol use. The pattern of associations was similar for males and females, with some differences in the associations between social support and alcohol use observed across age. Our findings highlight the important role of intermediate phenotypes and gene-environment interplay in the pathways of risk from genetic predispositions to complex alcohol use outcomes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000568DOI Listing
July 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use.

Behav Genet 2021 Sep 12;51(5):543-558. Epub 2021 Jun 12.

Department of Psychology, Virginia Commonwealth University, Box 842018, 806 W Franklin St, Richmond, VA, 23284, USA.

Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; M = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.
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http://dx.doi.org/10.1007/s10519-021-10067-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403154PMC
September 2021

Predicting alcohol use disorder remission: a longitudinal multimodal multi-featured machine learning approach.

Transl Psychiatry 2021 03 15;11(1):166. Epub 2021 Mar 15.

Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.

Predictive models for recovering from alcohol use disorder (AUD) and identifying related predisposition biomarkers can have a tremendous impact on addiction treatment outcomes and cost reduction. Our sample (N = 1376) included individuals of European (EA) and African (AA) ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA) who were initially assessed as having AUD (DSM-5) and reassessed years later as either having AUD or in remission. To predict this difference in AUD recovery status, we analyzed the initial data using multimodal, multi-features machine learning applications including EEG source-level functional brain connectivity, Polygenic Risk Scores (PRS), medications, and demographic information. Sex and ancestry age-matched stratified analyses were performed with supervised linear Support Vector Machine application and were calculated twice, once when the ancestry was defined by self-report and once defined by genetic data. Multifeatured prediction models achieved higher accuracy scores than models based on a single domain and higher scores in male models when the ancestry was based on genetic data. The AA male group model with PRS, EEG functional connectivity, marital and employment status features achieved the highest accuracy of 86.04%. Several discriminative features were identified, including collections of PRS related to neuroticism, depression, aggression, years of education, and alcohol consumption phenotypes. Other discriminated features included being married, employed, medication, lower default mode network and fusiform connectivity, and higher insula connectivity. Results highlight the importance of increasing genetic homogeneity of analyzed groups, identifying sex, and ancestry-specific features to increase prediction scores revealing biomarkers related to AUD remission.
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http://dx.doi.org/10.1038/s41398-021-01281-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960734PMC
March 2021

Associations between the CADM2 gene, substance use, risky sexual behavior, and self-control: A phenome-wide association study.

Addict Biol 2021 Nov 18;26(6):e13015. Epub 2021 Feb 18.

Behavioural Science Institute, Radboud University, The Netherlands.

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.
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http://dx.doi.org/10.1111/adb.13015DOI Listing
November 2021

Cannabis use in college: Genetic predispositions, peers, and activity participation.

Drug Alcohol Depend 2021 02 21;219:108489. Epub 2020 Dec 21.

Department of Psychology, Virginia Commonwealth University, Box 842018, Richmond, VA, 23284-2018, United States; College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Box 843092, Richmond, VA, 23284-3092, United States; Department of Human & Molecular Genetics, Virginia Commonwealth University, Box 980033, Richmond, VA, 23298-0033, United States. Electronic address:

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; N = 750) and African American (AA; N = 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.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369492PMC
February 2021

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Nat Commun 2020 11 3;11(1):5562. Epub 2020 Nov 3.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.
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http://dx.doi.org/10.1038/s41467-020-19265-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642344PMC
November 2020

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Using polygenic scores for identifying individuals at increased risk of substance use disorders in clinical and population samples.

Transl Psychiatry 2020 06 18;10(1):196. Epub 2020 Jun 18.

Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.

Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability. There is growing evidence that PRS may prove useful for early identification of those at increased risk for certain diseases. The current potential of PRS for alcohol use disorders (AUD) remains an open question. Using data from both a population-based sample [the FinnTwin12 (FT12) study] and a high-risk sample [the Collaborative Study on the Genetics of Alcoholism (COGA)], we examined the association between PRSs derived from genome-wide association studies (GWASs) of (1) alcohol dependence/alcohol problems, (2) alcohol consumption, and (3) risky behaviors with AUD and other substance use disorder (SUD) criteria. These PRSs explain ~2.5-3.5% of the variance in AUD (across FT12 and COGA) when all PRSs are included in the same model. Calculations of area under the curve (AUC) show PRS provide only a slight improvement over a model with age, sex, and ancestral principal components as covariates. While individuals in the top 20, 10, and 5% of the PRS distribution had greater odds of having an AUD compared to the lower end of the continuum in both COGA and FT12, the point estimates at each threshold were statistically indistinguishable. Those in the top 5% reported greater levels of licit (alcohol and nicotine) and illicit (cannabis and opioid) SUD criteria. PRSs are associated with risk for SUD in independent samples. However, usefulness for identifying those at increased risk in their current form is modest, at best. Improvement in predictive ability will likely be dependent on increasing the size of well-phenotyped discovery samples.
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http://dx.doi.org/10.1038/s41398-020-00865-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303212PMC
June 2020

Genetic and environmental influences on human height from infancy through adulthood at different levels of parental education.

Sci Rep 2020 05 14;10(1):7974. Epub 2020 May 14.

Department of Epidemiology, School of Public Health, Seoul National University, Seoul, 08826, Korea.

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.
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http://dx.doi.org/10.1038/s41598-020-64883-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224277PMC
May 2020

Population Attributable Fraction of Early Age of Onset of Alcohol Use in Alcohol Abuse and Dependence: A 3-Year Follow-Up Study in University Students.

Int J Environ Res Public Health 2020 03 24;17(6). Epub 2020 Mar 24.

Department of Psychology, Virginia Commonwealth University, Richmond, VA 23284, USA.

Background: we aimed to determine the risk factors and associated population attributable fractions (PAFs) for the age of onset of alcohol use and also to identify protective factors.

Methods: we analyzed follow-up data collected between autumn 2011 and spring 2016 ( = 5170) from the first two cohorts (2011, 2012) of the Spit for Science project. The dependent variables were alcohol abuse and dependence, and the independent variables were age of drinking onset, residence, ethnicity, religiosity, sexual orientation and work status. We determined the odds ratios (OR) using multilevel logistic regression for repeated measures in SPSSv.20.

Results: the early onset of alcohol use was associated with an increased risk of alcohol abuse and dependence among females (OR = 14.98; OR = 11.83) and males (OR = 7.41; OR = 6.24). The PAFs for the early onset of alcohol use in alcohol abuse and dependence were respectively 80.9% and 71.7% in females and 71.0% and 63.5% in males. Among females, being white (OR = 1.58; OR = 1.51), living off-campus (OR = 1.73; OR = 2.76) and working full-time (OR = 1.69; OR = 1.78) were also risk factors. Strong religious beliefs were found to protect males from alcohol abuse (OR = 0.58), while same-gender sexual orientation increased the risk among females (OR = 2.09).

Conclusion: delaying the age of onset by one year would reduce alcohol abuse among young adults.
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http://dx.doi.org/10.3390/ijerph17062159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142956PMC
March 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Which adolescent factors predict alcohol misuse in young adulthood? A co-twin comparisons study.

Addiction 2020 05 8;115(5):877-887. Epub 2020 Jan 8.

Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.

Background And Aims: Research on adolescent predictors of later alcohol misuse is typically conducted on samples of singletons, and associations may be confounded by between-family differences. To address potential confounding, we applied a co-twin comparison design to evaluate whether differences between co-twins in a wide array of adolescent risk factors predicted differences in young adult alcohol misuse.

Design: Longitudinal study in which associations between characteristics of the sample as adolescents were used to predict young adult alcohol misuse in individual-level analyses and co-twin comparisons.

Setting: Finland.

Participants: A total of 3402 individuals (1435 complete twin pairs; 36% monozygotic; 57% female) from the FinnTwin12 study.

Measurements: The young adult alcohol misuse outcome was a composite score of alcohol use and intoxication frequency. Adolescent predictors included factor scores representing academic performance, substance use, externalizing problems, internalizing problems, peer environment, physical health and relationship with parents; and single measures tapping alcohol expectancies, life events and pubertal development.

Findings: In individual-level analyses, individuals with higher adolescent substance use, externalizing problems, time with friends, peer deviance, sports involvement, sleeping difficulties, parental discipline, positive alcohol expectancies and difficulty of life events reported higher alcohol misuse in young adulthood (Ps < 0.019, R  = 0.0003-0.0310%). Conversely, those with higher adolescent internalizing problems, parent-child relationship quality and time with parents reported lower alcohol misuse (Ps < 0021, R  = 0.0018-0.0093%). The associations with adolescent substance use and alcohol expectancies remained significant in co-twin comparisons (Ps < 0.049, R  = 0.0019-0.0314%). Further, academic performance emerged as a significant predictor, such that individuals with higher grades compared with their co-twin reported higher young adult alcohol misuse (Ps < 0.029, R  = 0.0449-0.0533%).

Conclusions: Adolescent substance use, positive alcohol expectancies and higher academic performance appear to be robust predictors of later alcohol misuse.
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http://dx.doi.org/10.1111/add.14888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156309PMC
May 2020

Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis.

Addiction 2020 02 28;115(2):337-346. Epub 2019 Oct 28.

Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.

Background And Aims: The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis).

Design: Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families.

Setting: Six sites in the United States.

Participants: European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample.

Measurements: Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment.

Findings: In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R 0.13-0.20%).

Conclusions: Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).
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http://dx.doi.org/10.1111/add.14815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034661PMC
February 2020

Psychosocial moderation of polygenic risk for cannabis involvement: the role of trauma exposure and frequency of religious service attendance.

Transl Psychiatry 2019 10 21;9(1):269. Epub 2019 Oct 21.

Washington University School of Medicine, St. Louis, MO, 63110, USA.

Cannabis use and disorders (CUD) are influenced by multiple genetic variants of small effect and by the psychosocial environment. However, this information has not been effectively incorporated into studies of gene-environment interaction (GxE). Polygenic risk scores (PRS) that aggregate the effects of genetic variants can aid in identifying the links between genetic risk and psychosocial factors. Using data from the Pasman et al. GWAS of cannabis use (meta-analysis of data from the International Cannabis Consortium and UK Biobank), we constructed PRS in the Collaborative Study on the Genetics of Alcoholism (COGA) participants of European (N: 7591) and African (N: 3359) ancestry. The primary analyses included only individuals of European ancestry, reflecting the ancestral composition of the discovery GWAS from which the PRS was derived. Secondary analyses included the African ancestry sample. Associations of PRS with cannabis use and DSM-5 CUD symptom count (CUDsx) and interactions with trauma exposure and frequency of religious service attendance were examined. Models were adjusted for sex, birth cohort, genotype array, and ancestry. Robustness models were adjusted for cross-term interactions. Higher PRS were associated with a greater likelihood of cannabis use and with CUDsx among participants of European ancestry (p < 0.05 and p < 0.1 thresholds, respectively). PRS only influenced cannabis use among those exposed to trauma (R: 0.011 among the trauma exposed vs. R: 0.002 in unexposed). PRS less consistently influenced cannabis use among those who attend religious services less frequently; PRS × religious service attendance effects were attenuated when cross-term interactions with ancestry and sex were included in the model. Polygenic liability to cannabis use was related to cannabis use and, less robustly, progression to symptoms of CUD. This study provides the first evidence of PRS × trauma for cannabis use and demonstrates that ignoring important aspects of the psychosocial environment may mask genetic influences on polygenic traits.
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http://dx.doi.org/10.1038/s41398-019-0598-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803671PMC
October 2019

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

Brain Sci 2019 Oct 17;9(10). Epub 2019 Oct 17.

Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.

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 (-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, -values ranged from 10-10), 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.
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http://dx.doi.org/10.3390/brainsci9100280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826735PMC
October 2019

Evaluating Neighborhood, Social, and Genetic Influences on Precursors of Alcohol Use Risk Behavior in African American Adolescents.

Int J Environ Res Public Health 2019 08 24;16(17). Epub 2019 Aug 24.

School of Social Work, Virginia Commonwealth University, Richmond, VA 23284-9106, USA.

: Using a socioecological framework, we examined neighborhood and social stressors in concert with genetic risk for alcohol dependence in relation to externalizing behaviors, important precursors to alcohol-related problems. : We used data from African American adolescents and their caregivers in the Gene, Environment, and Neighborhood Initiative, a subsample of the Mobile Youth and Poverty Study. Participants for the current analyses included 112 adolescents who reported ever having at least one full drink of alcohol. Empirical Bayes scores were used to estimate neighborhood-level violence and transitions. Multivariate models tested main effects and then interactions of family stressors, discrimination, and genetic risk with the neighborhood variables. : In the main effects model, adolescent externalizing behaviors were positively associated with greater family stressors, more racial discrimination experiences, and genetic liability, while neighborhood variables were nonsignificant. We found three significant interactions. Specifically, the joint effects of neighborhood violence and transitions and between these neighborhood variables and family stressors were significantly associated with externalizing behaviors. : Our findings suggest genetic liability and complex interactions between neighborhood context and social stressors are important contributors that should be considered in the development of early prevention programs for adolescents who live in economically disadvantaged areas.
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http://dx.doi.org/10.3390/ijerph16173078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747126PMC
August 2019

Exploring how Family and Neighborhood Stressors Influence Genetic Risk for Adolescent Conduct Problems and Alcohol Use.

J Youth Adolesc 2020 Jul 12;49(7):1365-1378. Epub 2019 Aug 12.

Department of Psychology, Virginia Commonwealth University, 800W. Franklin, Room 202, Richmond, VA, 23284, USA.

Previous research suggests that genetic risk factors may predispose to conduct problems and alcohol use in adolescence. Whether genetic risk factors interact with social contexts has not been well characterized among African American adolescents. Data came from a subsample of the Genes, Environment, and Neighborhood Initiative study comprising 501 African American adolescents, including 151 lifetime drinkers (56% female, mean age = 16.3, SD = 1.4). Genetic risk was assessed with polygenic risk scores for alcohol dependence. Analyses explored interactions between genetic risk and self-reported alcohol use, conduct problems, life stressors, and other covariates. The effects of two gene-environment interactions (G × E) were tested in the sample of alcohol exposed adolescents; one on conduct problems and the other on alcohol use. There were significant associations between polygenic risk for alcohol dependence and conduct problems. A significant G × E interaction showed the impact of genetic risk on conduct problems was stronger under conditions of high exposure to family and neighborhood stressors. Among this sample of African American adolescents, genetic risk for alcohol dependence was not directly associated with alcohol use but was related to more conduct problems. Further, the effect of genetic risk interacted with stressors from the family and neighborhood, so that the effect of genetic risk on conduct problems was stronger for individuals who reported greater stressors.
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http://dx.doi.org/10.1007/s10964-019-01098-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012717PMC
July 2020

Unpacking Genetic Risk Pathways for College Student Alcohol Consumption: The Mediating Role of Impulsivity.

Alcohol Clin Exp Res 2019 10 26;43(10):2100-2110. Epub 2019 Aug 26.

From the, Department of Psychology, Virginia Commonwealth University, Richmond, Virginia.

Background: The period of college represents a particularly risky developmental stage with regard to alcohol use, as college students engage in more risky drinking behaviors than their noncollege peers, and such problematic alcohol use is associated with far-reaching negative consequences. Existing findings from genome-wide association studies (GWAS) indicate that alcohol consumption has a complex polygenic etiology. Currently, there is a lack of studies examining genetic risk for alcohol consumption using polygenic risk scores (PRS) in college samples. In this study, we examined whether alcohol-specific and risky behavior-related PRS were longitudinally associated with alcohol consumption among college students and whether this effect might be partially mediated by impulsivity domains.

Methods: The sample included n = 2,385 European ancestry (EA) and n = 1,153 African ancestry (AA) college students assessed over the course of 4 years. To indicate genetic risk, 2 PRS were created based on recent large-scale GWAS: alcohol consumption (Liu et al., 2019) -drinks per week (DPW)-PRS and risky behaviors (Linnér et al., 2019) -RISK-PRS. The main outcome was alcohol consumption, measured across 4 waves of follow-up data. The UPPS-P impulsivity subscales were examined as mediators of the genetic effect on alcohol consumption.

Results: The results from structural equation modeling showed that among EA students, both DPW-PRS and RISK-PRS had significant positive effects on alcohol consumption above and beyond UPPS dimensions and control variables. RISK-PRS explained larger portion of variance in alcohol consumption than DPW-PRS. RISK-PRS showed a significant indirect effect on alcohol consumption through sensation seeking and lack of perseverance; no significant indirect effect of DPW-PRS was found. No significant association of either PRS or alcohol consumption was found for AA participants.

Conclusions: The current results found that PRS related to more broadly defined risky behaviors predicted alcohol consumption across college years and that this association was partially mediated via dimensions of impulsivity.
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http://dx.doi.org/10.1111/acer.14157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779491PMC
October 2019

Polygenic risk for alcohol misuse is moderated by romantic partnerships.

Addiction 2019 10 30;114(10):1753-1762. Epub 2019 Jul 30.

Department of Psychology, Virginia Commonwealth University.

Background And Aims: Previous twin research suggests relationship status can moderate underlying genetic liability towards alcohol misuse. This paper examined: (1) whether genome-wide polygenic scores (GPS) for alcohol consumption are associated with alcohol misuse; (2) whether these GPS are moderated by romantic relationships (gene-environment interaction; G × E) and (3) whether G × E results are consistent across sex.

Design: Linear mixed-effects models were used to test associations between genome-wide polygenic scores, relationship status and alcohol use/misuse.

Setting: Finnish twins born between 1983 and 1987 identified through Finland's central population registry.

Participants: An intensively studied subset of Finnish Twin Study (FinnTwin12) during the young adult phase (aged 20-26 years). The analytical sample includes those with complete interview and genetic data (n = 1201).

Measurements: Key measurements included involvement in a romantic partnership, drinking frequency, intoxication frequency and DSM-IV alcohol dependence (AD) symptoms. Genome-wide polygenic scores (GPS) were created from available summary statistics from a large genome-wide association study (GWAS) of drinks per week.

Results: GPS predicted drinking frequency [b = 0.109; 95% confidence interval (CI) = 0.050, 0.168], intoxication frequency (b = 0.111; 95% CI = 0.054, 0.168) and AD symptoms (b = 0.123; 95% CI = 0.064, 0.182). Having a romantic relationship negatively influenced the association between GPS and drinking frequency (b = -0.105; 95% CI = -0.211, -0.001), intoxication frequency (b = -0.118; 95% CI = -0.220, -0.016) and AD symptoms (b = -0.119; 95% CI = -0.229, -0.009). There was a three-way interaction between sex, relationship status and GPS for intoxication frequency (b = 0.223; 95% CI = 0.013, 0.433), such that the reduced association between GPS and intoxication frequency for those in a relationship was only apparent in males. We found no evidence of three-way interactions for drinking frequency or AD symptoms.

Conclusions: Being in a romantic relationship reduced the association between genetic predisposition and drinking, high-risk drinking and alcohol problems. However, for high-risk drinking the protective effect was limited to males, mapping onto earlier findings suggesting that males benefit more from romantic partnerships.
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http://dx.doi.org/10.1111/add.14712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108791PMC
October 2019

The Family Check-up Intervention Moderates Polygenic Influences on Long-Term Alcohol Outcomes: Results from a Randomized Intervention Trial.

Prev Sci 2019 10;20(7):975-985

Department of Psychology, Virginia Commonwealth University, Box 842018, 806 West Franklin Street, Richmond, VA, 23284-2008, USA.

Alcohol problems are influenced by both genetic and environmental factors. Evidence from twin models and measured gene-environment interaction studies has demonstrated that the importance of genetic influences changes as a function of the environment. Research has also shown that family-centered interventions may protect genetically susceptible youth from developing substance use problems. In this study, we brought large-scale gene identification findings into an intervention study to examine gene-by-intervention effects. Using genome-wide polygenic scores derived from an independent genome-wide association study of adult alcohol dependence, we examined whether an adolescent family-centered intervention would moderate the effect of genetic risk for alcohol dependence on lifetime alcohol dependence in young adulthood, approximately 15 years after the start of intervention, among European American (N = 271; 48.3% in the intervention condition) and African American individuals (N = 192; 51.6% in the intervention condition). We found that among European American individuals, the intervention moderated the association between alcohol dependence polygenic scores and lifetime alcohol dependence diagnosis in young adulthood. Among participants in the control condition, higher alcohol dependence polygenic scores were associated with a greater likelihood of receiving an alcohol dependence diagnosis; in contrast, among participants in the intervention condition, there was no association between alcohol dependence polygenic scores and alcohol dependence diagnosis. No moderation effect was found among African Americans. These results demonstrate that modifying environments of genetically vulnerable youth could reduce the likelihood of developing alcohol dependence and underscore the significance of environmentally focused prevention and intervention efforts.
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http://dx.doi.org/10.1007/s11121-019-01024-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721991PMC
October 2019

Genes, Roommates, and Residence Halls: A Multidimensional Study of the Role of Peer Drinking on College Students' Alcohol Use.

Alcohol Clin Exp Res 2019 06 29;43(6):1254-1262. Epub 2019 Apr 29.

Department of Psychology, Virginia Commonwealth University, Richmond, Virginia.

Background: Peer drinking is one of the most robust predictors of college students' alcohol use and can moderate students' genetic risk for alcohol use. Peer effect research generally suffers from 2 problems: selection into peer groups and relying more on perceptions of peer alcohol use than peers' self-report. The goal of the present study was to overcome those limitations by capitalizing on a genetically informed sample of randomly assigned college roommates to examine multiple dimensions of peer influence and the interplay between peer effects and genetic predisposition on alcohol use, in the form of polygenic scores.

Methods: We used a subsample (n = 755) of participants from a university-wide, longitudinal study at a large, diverse, urban university. Participants reported their own alcohol use during fall and spring and their perceptions of college peers' alcohol use in spring. We matched individuals into their rooms and residence halls to create a composite score of peer-reported alcohol use for each of those levels. We examined multiple dimensions of peer influence and whether peer influence moderated genetic predisposition to predict college students' alcohol use using multilevel models to account for clustering at the room and residence hall level.

Results: We found that polygenic scores (β = 0.12), perceptions of peer drinking (β = 0.37), and roommates' self-reported drinking (β = 0.10) predicted alcohol use (all ps < 0.001), while average alcohol use across residence hall did not (β = -0.01, p = 0.86). We found no evidence for interactions between peer influence and genome-wide polygenic scores for alcohol use.

Conclusions: Our findings underscore the importance of genetic predisposition on individual alcohol use and support the potentially causal nature of the association between peer influence and alcohol use.
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http://dx.doi.org/10.1111/acer.14037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561118PMC
June 2019

The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample.

Alcohol Clin Exp Res 2019 06 21;43(6):1113-1125. Epub 2019 May 21.

Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri.

Background: Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples.

Methods: In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol-related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self-Rating of the Effects of Ethanol Questionnaire (SRE-T), DSM-IV alcohol dependence (DSM4AD), DSM-5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol-related outcomes. We performed mixed-effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD.

Results: PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R  = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R  = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R  = 0.49%), MAXD (Δmarginal R  = 0.31%), and SRE-T (Δmarginal R  = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e-5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant.

Conclusions: Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking.
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http://dx.doi.org/10.1111/acer.14064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560626PMC
June 2019

Parental Education and Genetics of BMI from Infancy to Old Age: A Pooled Analysis of 29 Twin Cohorts.

Obesity (Silver Spring) 2019 05 5;27(5):855-865. Epub 2019 Apr 5.

Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Objective: The objective of this study was to analyze how parental education modifies the genetic and environmental variances of BMI from infancy to old age in three geographic-cultural regions.

Methods: A pooled sample of 29 cohorts including 143,499 twin individuals with information on parental education and BMI from age 1 to 79 years (299,201 BMI measures) was analyzed by genetic twin modeling.

Results: Until 4 years of age, parental education was not consistently associated with BMI. Thereafter, higher parental education level was associated with lower BMI in males and females. Total and additive genetic variances of BMI were smaller in the offspring of highly educated parents than in those whose parents had low education levels. Especially in North American and Australian children, environmental factors shared by co-twins also contributed to the higher BMI variation in the low education level category. In Europe and East Asia, the associations of parental education with mean BMI and BMI variance were weaker than in North America and Australia.

Conclusions: Lower parental education level is associated with higher mean BMI and larger genetic variance of BMI after early childhood, especially in the obesogenic macro-environment. The interplay among genetic predisposition, childhood social environment, and macro-social context is important for socioeconomic differences in BMI.
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http://dx.doi.org/10.1002/oby.22451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478550PMC
May 2019

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.

Nat Neurosci 2018 12 26;21(12):1656-1669. Epub 2018 Nov 26.

NIH/NIAAA, Laboratory of Neurogenetics, Bethesda, MD, USA.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10) and African ancestries (rs2066702; P = 2.2 × 10). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
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http://dx.doi.org/10.1038/s41593-018-0275-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430207PMC
December 2018

Exploring the relationship between polygenic risk for cannabis use, peer cannabis use and the longitudinal course of cannabis involvement.

Addiction 2019 04 1;114(4):687-697. Epub 2019 Jan 1.

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.

Background And Aims: Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories from ages 12-30 years and perceived peer cannabis use at ages 12-17 years.

Design: Mixed-effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership and perceived peer cannabis use.

Setting: United States.

Participants: From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1167 individuals aged 12-26 years at their baseline (i.e. first) interview.

Measurements: Key measurements included life-time cannabis use (yes/no), frequency of past 12-month cannabis use, maximum life-time frequency of cannabis use, cannabis use disorder (using DSM-5 criteria) and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (n = 162 082) genome-wide association study (GWAS) of cannabis use.

Findings: Three trajectories reflecting no/low (n = 844), moderate (n = 137) and high (n = 186) use were identified. PRS were significantly associated with trajectory membership [P = 0.002-0.006, maximum conditional R  = 1.4%, odds ratios (ORs) = 1.40-1.49]. Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users [OR = 1.35, 95% confidence interval (CI) = 1.04, 1.75, P = 0.023]. Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR = 1.50-4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (P < 0.01).

Conclusions: Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults.
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http://dx.doi.org/10.1111/add.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411425PMC
April 2019

Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence.

Neuropsychopharmacology 2018 12 6;43(13):2521-2531. Epub 2018 Sep 6.

Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA.

Understanding how ethanol actions on brain signal transduction and gene expression lead to excessive consumption and addiction could identify new treatments for alcohol dependence. We previously identified glycogen synthase kinase 3-beta (Gsk3b) as a member of a highly ethanol-responsive gene network in mouse medial prefrontal cortex (mPFC). Gsk3b has been implicated in dendritic function, synaptic plasticity and behavioral responses to other drugs of abuse. Here, we investigate Gsk3b in rodent models of ethanol consumption and as a risk factor for human alcohol dependence. Stereotactic viral vector gene delivery overexpression of Gsk3b in mouse mPFC increased 2-bottle choice ethanol consumption, which was blocked by lithium, a known GSK3B inhibitor. Further, Gsk3b overexpression increased anxiety-like behavior following abstinence from ethanol. Protein or mRNA expression studies following Gsk3b over-expression identified synaptojanin 2, brain-derived neurotrophic factor and the neuropeptide Y Y5 receptor as potential downstream factors altering ethanol behaviors. Rat operant studies showed that selective pharmacologic inhibition of GSK3B with TDZD-8 dose-dependently decreased motivation to self-administer ethanol and sucrose and selectively blocked ethanol relapse-like behavior. In set-based and gene-wise genetic association analysis, a GSK3b-centric gene expression network had significant genetic associations, at a gene and network level, with risk for alcohol dependence in humans. These mutually reinforcing cross-species findings implicate GSK3B in neurobiological mechanisms controlling ethanol consumption, and as both a potential risk factor and therapeutic target for alcohol dependence.
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http://dx.doi.org/10.1038/s41386-018-0202-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224501PMC
December 2018

Alcohol Metabolizing Polygenic Risk for Alcohol Consumption in European American College Students.

J Stud Alcohol Drugs 2018 07;79(4):627-634

Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090104PMC
July 2018

Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts.

PLoS One 2018 12;13(7):e0200140. Epub 2018 Jul 12.

Norwegian Institute of Public Health, Oslo, Norway.

Background: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background.

Methods And Findings: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade.

Conclusions: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200140PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042712PMC
January 2019
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