Polygenic risk score for problematic alcohol use predicts heavy drinking and alcohol use disorder symptoms in young adulthood after accounting for adolescent alcohol use and parental alcohol use disorder.

BACKGROUND: Genome-wide association studies (GWAS) have identified hundreds of loci associated with alcohol-related traits. GWAS permit the calculation of polygenic risk scores (PRS), which aggregate genetic risk for a trait across the genome. To evaluate the usefulness of a PRS for problematic alcohol use (PAU)-which subsumes alcohol use disorder (AUD) and alcohol-related problems-we tested whether this PRS predicted heavy drinking and alcohol problems after accounting for family history of AUD and prior drinking history, robust and established predictors of PAU. METHODS: Participants (N=665) were European-ancestry members of the Michigan Longitudinal Study, a prospective family study with high rates (65%) of parental AUD. Participants reported their frequency of alcohol use, maximum drinks consumed in a 24-hour period, and alcohol use problems at four assessments in adolescence and young adulthood (11-29 years old). We used polygenic prediction via Bayesian regression and continuous shrinkage priors to create a PAU PRS using summary statistics from a meta-GWAS of PAU. RESULTS: After adjusting for demographic covariates, parental AUD, and drinking and alcohol use problems in early and mid/late adolescence, the PAU PRS was significantly associated with alcohol-related problems in young adulthood (ß=.08, p=.047; R2=0.6%). The PAU PRS also had a significant indirect effect on alcohol use problems in young adulthood through earlier drinking and alcohol use problems (ß=.02, p=.03). CONCLUSIONS: The PAU PRS predicted alcohol problems in young adulthood after accounting for parental history of AUD and alcohol use in adolescence, providing evidence that genetic data uniquely inform the etiology of alcohol problems.

Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-alcohol-related problems comorbidity also contribute to PTSD- alcohol consumption. METHODS: We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD and a range of alcohol consumption-related and alcohol-related problems phenotypes. RESULTS: In EAs, there were positive genetic correlations between PTSD phenotypes and alcohol-related problems phenotypes (e.g. Alcohol Use Disorders Identification Test (AUDIT) problem score) (rGs: 0.132-0.533, all FDR adjusted p < 0.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (e.g. drinks per week) were negatively associated or non-significant (rGs: -0.417 to -0.042, FDR adjusted p: <0.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for alcohol-related problems: -0.275 to 0.266, FDR adjusted p: NS, alcohol consumption-related: 0.145-0.699, FDR adjusted p: NS). CONCLUSIONS: These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems. Discussion around needing improved methods to better estimate heritabilities and genetic correlations in diverse and admixed ancestry samples is provided.

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

BACKGROUND: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-ß-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING: Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

Behavioral genetics of alcohol's effects in three zebrafish (Danio rerio) populations.

Alcohol abuse is one of the most dangerous and serious problems for patients and society. Interpopulation studies are important in understanding how genetic background contributes to the effects of alcohol. In this study, we applied a chronic alcohol exposure protocol in three zebrafish populations (Danio rerio; both sexes; AB, TU, and outbred fish - OB). We analyzed the behavioral responses and mRNA expression involved in neurotransmitter metabolism - th1, tph1, ache, ada1, gaba1, gad1b, and bdnf. Locomotion patterns were similar between populations (increased speed after acute alcohol and unaltered locomotion after chronic and withdrawal treatments). All populations exhibited increased expression of genes associated with locomotion (th1, gad1b, and gaba1) after acute alcohol exposure. Anxiety-like responses increased in AB and TU fish during withdrawal and decreased in AB fish after acute alcohol exposure. Genes related to anxiety-like behavior (tph1 and ada1) were overexpressed in AB and TU fish after acute and withdrawal treatments, while OB fish exhibited unaltered responses. Bdnf levels decreased during withdrawal in AB and OB fish, while TU showed upregulated levels in both chronic and withdrawal treatments. Our results suggest that zebrafish populations respond differently to alcohol exposure, which may contribute to understanding the mechanisms underlying alcohol use and dependence. Moreover, we found that a more diverse genetic background (OB) was related to higher variability in behavioral and mRNA expression, demonstrating that inbred populations (AB and TU) may be useful tools in identifying alcohol use and abuse mechanisms.

Long non­coding RNA­based risk scoring system predicts prognosis of alcohol­related hepatocellular carcinoma.

Increasing evidence suggests that long non-coding RNAs (lncRNAs) serve a crucial role in predicting prognosis for hepatocellular carcinoma (HCC). However, prognostic performance may not be the same for alcohol­related HCC. The aim of the present study was to screen prognosis­associated lncRNAs and construct a risk scoring system for alcohol­related HCC. The expression profiles of lncRNAs in 113 patients with alcohol­related HCC and 224 with non­alcohol­related HCC were obtained from The Cancer Genome Atlas (TCGA) database and screened for differentially expressed lncRNAs. Cox regression analysis was performed to identify prognosis­associated lncRNAs and select the optimal lncRNA model. A risk scoring system was established to calculate the risk score for each patient. The prognostic ability of this system was tested. Functional enrichment analysis was performed for genes that were highly associated with lncRNA expression. A total of 102 differentially expressed lncRNAs were identified between alcohol­related and non­alcohol­related HCC. Four lncRNAs (AC012640.1, AC013451.2, AC062004.1 and LINC02334) were used to construct the risk assessment model to predict overall survival (OS), and five lncRNAs (ERVH48­1, LINC02043, LINC01605, AC062004.1 and AL139385) were used to predict recurrence­free survival (RFS). Patients were assigned to high­ or low­risk groups according to the risk score. OS in the high­risk group was significantly shorter than that of the low­risk group. The area under the receiver operating characteristic (ROC) curve of risk scoring systems was >0.7. The risk score was an independent prognostic factor for alcohol­related HCC. Functional enrichment analysis demonstrated that lncRNA­related genes found in this system were mainly involved in chemical carcinogenesis, drug metabolism, and the cell cycle. In conclusion, this study developed and validated a prognostic scoring system for alcohol­related HCC based on lncRNAs.

Family History of Alcohol Abuse Associated with Higher Impulsivity in Patients with Alcohol Use Disorder: A Multisite Study.

BACKGROUND: Alcohol use disorder (AUD) is to a high degree heritable, and in clinical practice it is common to assert presence of alcohol abuse family history (FH) in treatment-seeking AUD patients. Patients with AUD also exhibit cognitive deficits, including elevated impulsivity and impairments in executive functions (EF), but less is known regarding the relation between FH and these cognitive domains. The aim of the current study was to investigate if alcohol abuse FH in AUD patients is associated with a specific cognitive profile. METHODS: Patients with AUD (n = 197) from Sweden (n = 106) and Belgium (n = 91) were recruited. Self-rated impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). EF assessed were response inhibition (stop signal task), attention (rapid visual processing task), and working memory (digit span). A series of linear regression models were run to explore the effect of FH on cognitive outcomes. RESULTS: A FH of alcohol abuse was associated with elevated score in self-rated impulsivity assessed by the BIS, with the greatest effect on the subscale of nonplanning. There was no statistically significant association between FH and any of the other neuropsychological task outcomes. CONCLUSION: Presence of alcohol abuse FH within AUD patients could be a marker of higher impulsivity, which may have clinical implications regarding diagnostic evaluation and treatment.

Type 1 equilibrative nucleoside transporter (ENT1) regulates sex-specific ethanol drinking during disruption of circadian rhythms.

Disruptions in circadian rhythms are risk factors for excessive alcohol drinking. The ethanol-sensitive adenosine equilibrative nucleoside transporter type 1 (ENT1, slc29a1) regulates ethanol-related behaviors, sleep, and entrainment of circadian rhythms. However, the mechanism underlying the increased ethanol consumption in ENT1 knockout (KO) mice in constant light (LL) and whether there are sex differences in ethanol consumption in ENT1 mice are less studied. Here, we investigated the effects of loss of ENT1, LL, and sex on ethanol drinking using two-bottle choice. In addition, we monitored the locomotor activity rhythms. We found that LL increased ethanol drinking and reduced accumbal ENT1 expression and adenosine levels in male but not female mice, compared with control mice. Interestingly, only LL-exposed male, not female, ENT1 KO mice exhibited higher ethanol drinking and a longer circadian period with a higher amplitude compared with wild-type (WT) mice. Furthermore, viral-mediated rescue of ENT1 expression in the NAc of ENT1 KO mice reduced ethanol drinking, demonstrating a possible causal link between ENT1 expression and ethanol drinking in males. Together, our findings indicate that deficiency of ENT1 expression contributes to excessive ethanol drinking in a sex-dependent manner.

Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse striatum by chronic ethanol exposure.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu2) is a Gi/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu2-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu2-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu2-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu2 fully rescues mGlu2-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu2-LTD. We did not observe a reduction of mGlu2 mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

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

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.

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis.

The pivotal role of the extracellular matrix (ECM) as both a cause and consequence of liver fibrosis is striking. However, mechanotransducer molecules and profibrogenic factors induced by liver stiffness are still unclear. The current study aimed to investigate liver stiffness and its correlation with the expression of the transcriptional coactivator with PDZ-binding motif (TAZ) and serum osteopontin (OPN) in human cirrhosis. In this case-control study, liver tissue stiffness was determined using atomic force microscopy in cirrhotic livers (n = 38) of different etiologies and in controls (n = 10). Immunohistochemical and qRT-PCR analyses were performed to analyze TAZ expression. Besides, western blotting and ELISA were performed to assess liver Indian hedgehog and serum OPN levels, respectively. Liver stiffness, TAZ expression, and hepatic gene expression and serum protein levels of OPN were significantly increased in patients with cirrhosis compared with the control groups (all P < 0.001), specifically in autoimmune- and alcohol-related cirrhosis. In cirrhotic patients, liver stiffness was significantly associated with the expression of nuclear TAZ and OPN. The correlation between matrix stiffness as a mechanical property, TAZ as a potential mechanotransducer, and OPN as a matricellular factor suggests possible effects of mechanical features of the ECM on the expression of the aforementioned profibrogenic markers, which is predominant in autoimmune- and alcohol-related cirrhosis.

The Association of Impulsivity and Family History of Alcohol Use Disorder on Alcohol Use and Consequences.

BACKGROUND: Extensive research indicates that having a positive family history of alcohol use disorder (FHP) and impulsivity are 2 risk factors for problem drinking. To our knowledge, no study has investigated which facets of impulsivity interact with family history to increase risk for problem drinking. The goal of this study was to: (i) examine whether FHP individuals with higher levels of impulsivity are more likely to engage in problematic drinking, and (ii) identify which facets of impulsivity interact with FHP to increase risk for problems. METHODS: The data consisted of a combined sample of 757 participants (50% female, 73% White, mean age = 32.85, SD = 11.31) drawn from the Transdisciplinary Tobacco Use Research Center and the Center for the Translational Neuroscience of Alcohol. Analyses of covariance and cumulative logistic regression models investigated the association of family history and impulsivity-related traits with drinking quantity, frequency, and alcohol-related problems. Models were adjusted for age, sex, race, ethnic group, education level, and data source. RESULTS: Significant interactions between impulsivity and family history were found for measures of alcohol-related problems. Specifically, there was a stronger positive association of Barratt Impulsiveness Scale (BIS) poor self-regulation with interpersonal, F(1, 504) = 6.27, p = 0.01, and impulse control alcohol-related problems, F(1, 504) = 6.00, p = 0.01, among FHP compared to FHN individuals. Main effects of family history and impulsivity on alcohol quantity and frequency of use and problems were also found. CONCLUSIONS: These findings suggest that having both a family history of AUD and high BIS poor self-regulation is more strongly associated with alcohol-related consequences in the interpersonal and impulse control domains. Given the heterogeneity of impulsivity, these findings highlight the need for additional research to examine which facets of impulsivity are associated with which alcohol outcomes to narrow phenotypic risk for alcohol misuse.

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

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 R2  = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2  = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2  = 0.49%), MAXD (Δmarginal R2  = 0.31%), and SRE-T (Δmarginal R2  = 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 R2 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.

Brain Imaging-Guided Analysis Reveals DNA Methylation Profiles Correlated with Insular Surface Area and Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is a wide-spread, heritable brain disease, but few studies have linked genetic variants or epigenetic factors to brain structures related to AUD in humans, due to many factors including the high-dimensional nature of imaging and genomic data. METHODS: To provide potential insights into the links among epigenetic regulation, brain structure, and AUD, we have performed an integrative analysis of brain structural imaging and blood DNA methylome data from 52 AUD and 58 healthy control (HC) subjects collected in the Nathan Kline Institute-Rockland Sample. RESULTS: We first found that AUD subjects had significantly larger insular surface area than HC in both left and right hemispheres. We then found that 7,827 DNA methylation probes on the HumanMethylation450K BeadChip had significant correlations with the right insular surface area (false discovery rate [FDR] < 0.05). Furthermore, we showed that 44 of the insular surface area-correlated methylation probes were also strongly correlated with AUD status (FDR < 0.05). These AUD-correlated probes are annotated to 36 protein-coding genes, with 16 genes (44%) having been reported by others to be related to AUD or alcohol response, including TAS2R16 and PER2. The remaining 20 genes, in particular ARHGAP22, might represent novel genes involved in AUD or responsive to alcohol. CONCLUSIONS: We have identified 36 insular surface area- and AUD-correlated protein-coding genes that are either known to be AUD- or alcohol-related or not yet reported by prior studies. Therefore, our study suggests that the brain imaging-guided epigenetic analysis has a potential of identifying possible epigenetic mechanisms involved in AUD.

Relapse of drunk driving and association with traffic accidents, alcohol-related problems and biomarkers of impulsivity.

OBJECTIVE: Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. METHODS: We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. RESULTS: The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. CONCLUSIONS: Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.

Reliability and validity of an internalizing symptom scale based on the adolescent and adult Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA).

BACKGROUND: The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) is an interview that assesses psychiatric symptoms and diagnoses, including substance use disorders and anxiety and mood (i.e., internalizing) disorders. Although the SSAGA is widely used, there exists no overall internalizing characteristics scale based on items drawn from SSAGA's mood and anxiety disorder sections. OBJECTIVES: To design and assess a SSAGA-based measurement instrument capturing the overall internalizing dimension that underlies more specific internalizing conditions. METHODS: We developed, assessed, and characterized a new scale for measuring internalizing problematic characteristics derived from the SSAGA interview. All samples were drawn from the Collaborative Studies on the Genetics of Alcoholism, a prospective multi-site genetic study of families at high risk for alcohol use disorders. All participants taking part in the study between September 2005 and September 2017 were eligible (n = 904, 52.2% female). RESULTS: The scale had adequate internal consistency (ordinal α = 0.85, 95% CI = [0.81, 0.89]). Construct validity was supported by its association with other measures of internalizing characteristics (Internalizing Scale from Achenbach Self Reports; Neuroticism Scale from the Neuroticism-Extraversion-Openness Five-Factor Personality Inventory). Several indices of alcohol, marijuana, and nicotine misuse were also positively associated with Internalizing Scale scores. CONCLUSIONS: The Internalizing Scale has very good psychometric properties and can be used in studies that incorporate the SSAGA interview to study the association between internalizing characteristics and problematic alcohol and other substance use. These associations can potentially be utilized to identify individuals at risk for substance problems and to design treatments targeting such individuals.

Neighborhood density of alcohol outlets moderates genetic and environmental influences on alcohol problems.

BACKGROUND AND AIMS: Geographic differences in rates of alcohol use disorder suggest that environmental factors and gene-environment interactions are likely to play an important role in its genesis. We aimed to examine whether living in a community with more alcohol outlets would facilitate the expression of the genetic propensity to develop alcohol problems. DESIGN: Cross-sectional twin/sibling study. SETTING: United States. PARTICIPANTS: The participants were 18-26-year-old twin, full- and half-sibling pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. MEASUREMENTS: Participants completed in-home interviews in which past year alcohol problems were assessed. Alcohol outlet densities were extracted from state-level liquor license databases aggregated at the census tract level. FINDINGS: There was evidence that estimates of genetic and environmental influences on alcohol problems varied as a function of the density of alcohol outlets in the community. The heritability of alcohol problems for those residing in a neighborhood with more than 10 on-premises outlets was 78% (95% confidence limits = 52-100%), compared with 11% (95% confidence limits = 0-29%) for those in a neighborhood with no on-premises outlets. This moderating effect of alcohol outlet density was not explained by state of residence, population density or neighborhood socio-demographic characteristics. CONCLUSIONS: Individuals who are genetically predisposed to develop alcohol problems may be especially sensitive to the influence of many alcohol outlets in their community.

Associações entre polimorfismos genéticos da álcool: desidrogenase e o transtorno por uso de álcool / Associations between genetic polymorphisms of alcohol: dehydrogenase and alcohol use disorder

O transtorno por uso de álcool (TUA) é influenciado pela genética, principalmente na metabolização do etanol. Os genes da álcool desidrogenase (ADH1B/ADH1C), enzima que transforma o etanol, apresentam SNPs (single nucleotide polymorphisms) que resultam em isoenzimas com diferentes taxas catalíticas. Estudos demonstraram que os SNPs Arg48His, Arg370Cys, Arg272Gln e Ile350Val contribuem para o TUA. Este artigo revisou os estudos que investigaram SNPs em ADH1B (Arg48His/Arg370Cys) e ADH1C (Arg272Gln/Ile350Val), bem como avaliou as variações nas frequências alélicas desses genes e a influência no TUA nas diferentes populações no mundo. As frequências alélicas dos polimorfismos foram comparadas pelos testes qui-quadrado de Pearson e exato de Fisher (p < 0,05). O SNP Arg48His confere proteção para o TUA em euroamericanos, latino-americanos, europeus, brasileiros, asiáticos e australianos. O SNP Arg370Cys confere proteção para o TUA em afrodescendentes. Os SNPs Arg272Gln e Ile350Val predispõem o TUA principalmente em europeus. Os SNPs Arg48His, Arg370Cys e Arg272Gln/Ile350Val foram mais frequentes em amostras de leste-asiáticos (69,7%), africanos (19,1%) e europeus (40,5%), respectivamente (p < 0,01). Os diferentes alelos dos genes ADH1B/ADH1C devido a SNPs têm uma importante contribuição no TUA. As frequências desses alelos variam conforme a população, resultando em diferentes efeitos no TUA. (AU)

Alcohol use disorder (AUD) is influenced by genetics, especially in the metabolism of ethanol. The ethanol dehydrogenase genes (ADH1B/ADH1C), which convert ethanol, have single nucleotide polymorphisms (SNPs) that result in isoenzymes with different catalytic rates. Studies have shown that the Arg48His, Arg370Cys, Arg272Gln, and Ile350Val SNPs contribute to AUD. This article reviewed the studies that investigated SNPs in ADH1B (Arg48His/Arg370Cys) and ADH1C (Arg272Gln/Ile350Val) and evaluated variations in the allele frequencies of these genes and their influence on AUD in different populations worldwide. The allele frequencies of the polymorphisms were compared by Pearson's chi-square and Fisher's exact tests (p < 0.05). The Arg48His SNP provides protection against AUD in Euro-Americans, Latin Americans, Europeans, Brazilians, Asians, and Australians. The Arg370Cys SNP provides protection against AUD in Afro-descendants. The Arg272Gln and Ile350Val SNPs predispose to AUD mainly in Europeans. The Arg48His, Arg370Cys, and Arg272Gln/Ile350Val SNPs were more frequent in East Asians (69.7%), Africans (19.1%), and Europeans (40.5%), respectively (p < 0.01). The different alleles of the ADH1B/ADH1C genes due to SNPs make an important contribution to AUD. The frequencies of these alleles vary among different populations, resulting in different effects on AUD..(AU)

Associations Between Alcohol Involvement and Drive for Thinness and Body Dissatisfaction in Adolescent Twins: A Bivariate Twin Study.

BACKGROUND: Alcohol involvement has familial associations with bulimic symptoms (i.e., binge eating, inappropriate compensatory behaviors), with several studies indicating a genetic overlap between the two. It is unclear whether overlapping familial risk with alcohol involvement extends to other eating disorder symptoms. Understanding the genetic overlap between alcohol involvement and other eating disorder symptoms may aid in more targeted interventions for comorbid alcohol use-eating disorder symptoms. Thus, we investigated associations between alcohol involvement and 2 core eating disorder symptoms: drive for thinness and body dissatisfaction in adolescent female and male twins. METHODS: We assessed 3 levels of alcohol involvement: alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency via self-report. The Eating Disorder Inventory-II assessed drive for thinness and body dissatisfaction. Sex-specific biometrical twin modeling examined the genetic overlap between alcohol involvement and eating disorder symptoms. RESULTS: Phenotypic associations between alcohol involvement, drive for thinness, and body dissatisfaction were significantly greater in girls compared with boys. A majority of the associations between alcohol involvement, drive for thinness, and body dissatisfaction in girls, but not boys, met our threshold for twin modeling (phenotypic r > 0.20). Moderate genetic correlations were observed between the 3 aspects of alcohol involvement and drive for thinness. Moderate genetic correlations were observed between alcohol use and intoxication frequency and body dissatisfaction. CONCLUSIONS: Together with the literature on alcohol involvement and bulimic symptoms, these findings suggest a generalized association between alcohol involvement and eating disorder symptoms in girls, whereas this association may be symptom specific in boys. Genetic correlations indicate that the amount and direction of this genetic overlap differs across specific symptoms. When intervening on comorbid alcohol involvement and eating disorder symptoms, it may be important to target-specific eating disorder symptoms.

Cross-species molecular dissection across alcohol behavioral domains.

This review summarizes the proceedings of a symposium presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference held in Volterra, Italy on May 9-12, 2017. Psychiatric diseases, including alcohol-use disorders (AUDs), are influenced through complex interactions of genes, neurobiological pathways, and environmental influences. A better understanding of the common neurobiological mechanisms underlying an AUD necessitates an integrative approach, involving a systematic assessment of diverse species and phenotype measures. As part of the World Congress on Stress and Alcoholism, this symposium provided a detailed account of current strategies to identify mechanisms underlying the development and progression of AUDs. Dr. Sean Farris discussed the integration and organization of transcriptome and postmortem human brain data to identify brain regional- and cell type-specific differences related to excessive alcohol consumption that are conserved across species. Dr. Brien Riley presented the results of a genome-wide association study of DSM-IV alcohol dependence; although replication of genetic associations with alcohol phenotypes in humans remains challenging, model organism studies show that COL6A3, KLF12, and RYR3 affect behavioral responses to ethanol, and provide substantial evidence for their role in human alcohol-related traits. Dr. Rob Williams expanded upon the systematic characterization of extensive genetic-genomic resources for quantifying and clarifying phenotypes across species that are relevant to precision medicine in human disease. The symposium concluded with Dr. Robert Hitzemann's description of transcriptome studies in a mouse model selectively bred for high alcohol ("binge-like") consumption and a non-human primate model of long-term alcohol consumption. Together, the different components of this session provided an overview of systems-based approaches that are pioneering the experimental prioritization and validation of novel genes and gene networks linked with a range of behavioral phenotypes associated with stress and AUDs.