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.

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.

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.

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.

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.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

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.

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.

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.

Predictive modeling of miRNA-mediated predisposition to alcohol-related phenotypes in mouse.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that bind messenger RNAs and promote their degradation or repress their translation. There is increasing evidence of miRNAs playing an important role in alcohol related disorders. However, the role of miRNAs as mediators of the genetic effect on alcohol phenotypes is not fully understood. We conducted a high-throughput sequencing study to measure miRNA expression levels in alcohol naïve animals in the LXS panel of recombinant inbred (RI) mouse strains. We then combined the sequencing data with genotype data, microarry gene expression data, and data on alcohol-related behavioral phenotypes such as 'Drinking in the dark', 'Sleep time', and 'Low dose activation' from the same RI panel. SNP-miRNA-gene triplets with strong association within the triplet that were also associated with one of the 4 alcohol phenotypes were selected and a Bayesian network analysis was used to aggregate results into a directed network model. RESULTS: We found several triplets with strong association within the triplet that were also associated with one of the alcohol phenotypes. The Bayesian network analysis found two networks where a miRNA mediates the genetic effect on the alcohol phenotype. The miRNAs were found to influence the expression of protein-coding genes, which in turn influences the quantitative phenotypes. The pathways in which these genes are enriched have been previously associated with alcohol-related traits. CONCLUSION: This work enhances association studies by identifying miRNAs that may be mediating the association between genetic markers (SNPs) and the alcohol phenotypes. It suggests a mechanism of how genetic variants are affecting traits of interest through the modification of miRNA expression.

Dynamic changes in gene expression and alternative splicing mediate the response to acute alcohol exposure in Drosophila melanogaster.

Environmental changes typically cause rapid gene expression responses in the exposed organisms, including changes in the representation of gene isoforms with different functions or properties. Identifying the genes that respond to environmental change, including in genotype-specific ways, is an important step in treating the undesirable physiological effects of stress, such as exposure to toxins or ethanol. Ethanol is a unique environmental stress in that chronic exposure results in permanent physiological changes and the development of alcohol use disorders. Drosophila is a classic model for deciphering the mechanisms of the response to alcohol exposure, as it meets the criteria for the development of alcohol use disorders, and has similar physiological underpinnings with vertebrates. Because many studies on the response to ethanol have relied on a priori candidate genes, broad surveys of gene expression and splicing are required and have been investigated here. Further, we expose Drosophila to ethanol in an environment that is genetically, socially, and ecologically relevant. Both expression and splicing differences, inasmuch as they can be decomposed, contribute to the response to ethanol in Drosophila melanogaster. However, we find that while D. melanogaster responds to ethanol, there is very little genetic variation in how it responds to ethanol. In addition, the response to alcohol over time is dynamic, suggesting that incorporating time into studies on the response to the environment is important.

Validation of Alcohol Flushing Questionnaires in Determining Inactive Aldehyde Dehydrogenase-2 and Its Clinical Implication in Alcohol-Related Diseases.

BACKGROUND: Our aim was to validate alcohol flushing questionnaires in detecting inactive ALDH2 (ALDH2*1/*2 or ALDH2*2/*2). METHODS: Two study sets were established; in study set 1, 210 healthy male subjects (age 22 to 59 years) were enrolled; in study set 2, 756 subjects were enrolled who received esophagogastroduodenoscopy to evaluate their dyspeptic symptoms or as part of a gastric cancer screening program. Subjects in study sets 1 and 2 completed the modified alcohol flushing questionnaires of Yokoyama and colleagues (, ). Polymerase chain reaction-restriction fragment length polymorphism method was used to determine ALDH2 genotype. RESULTS: In study set 1, 29.0% (61 of 210) had inactive ALDH2. The sensitivity and specificity of the modified alcohol flushing questionnaire for detecting inactive ALDH2 were 95.1 and 76.5%, respectively. Drinking problems negatively correlated with positive alcohol flushing response and inactive ALDH2 (all p-values < 0.05). In study set 2, the sensitivity and specificity of the alcohol flushing questionnaire for detecting inactive ALDH2 were 78.9 and 82.1%, respectively. Interestingly, drinking ≥7 units/wk in men or ≥3.5 units/wk in women significantly increased the risk of benign gastric ulcer (BGU) among positive alcohol flushers (odds ratio, 8.97; 95% confidence interval, 1.38 to 58.30), but not among negative alcohol flushers. CONCLUSIONS: Simple flushing questionnaires may be administered to the Korean population as a screening tool in detecting individuals who carry inactive ALDH2. Alcohol flushing response negatively correlates with drinking problems and can modify the risk for BGU by alcohol intake.

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.

Heavy drinking among individuals with HIV: who drinks despite knowledge of the risk?

Heavy drinking can cause medical problems for individuals with HIV, and drinking despite medical contraindications indicates problem use. However, little is known about which individuals with HIV drink despite knowledge of health problems. This study utilizes two subsamples of individuals with HIV from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III): those reporting at least one drink (a) in their lifetime (n = 205) or (b) in the past year (n = 166). Participants reported on drinking despite health problems and psychopathology in the past year and in their lifetime, and family history of alcohol problems. Individuals with a drug use disorder (Adjusted Odds Ratios [AORs] = 3.56-12.65), major depressive disorder (AORs = 10.18-10.55), or a family history of alcohol problems (AORs = 33.60-96.01) were more likely to drink despite health problems. Anxiety and personality disorders did not increase risk. Individuals with HIV with drug use disorders or major depressive disorder are more likely to drink despite health problems. Individuals with a family history of alcohol problems were also more likely to do so, although further research is needed given large confidence intervals. Future research should consider how to help these individuals avoid alcohol-related harm.

ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective.

The occurrence of more than 200 diseases, including cancer, can be attributed to alcohol drinking. The global cancer deaths attributed to alcohol-consumption rose from 243,000 in 1990 to 337,400 in 2010. In 2010, cancer deaths due to alcohol consumption accounted for 4.2% of all cancer deaths. Strong epidemiological evidence has established the causal role of alcohol in the development of various cancers, including esophageal cancer, head and neck cancer, liver cancer, breast cancer, and colorectal cancer. The evidence for the association between alcohol and other cancers is inconclusive. Because of the high prevalence of ALDH2*2 allele among East Asian populations, East Asians may be more susceptible to the carcinogenic effect of alcohol, with most evidence coming from studies of esophageal cancer and head and neck cancer, while data for other cancers are more limited. The high prevalence of ALDH2*2 allele in East Asian populations may have important public health implications and may be utilized to reduce the occurrence of alcohol-related cancers among East Asians, including: 1) Identification of individuals at high risk of developing alcohol-related cancers by screening for ALDH2 polymorphism; 2) Incorporation of ALDH2 polymorphism screening into behavioral intervention program for promoting alcohol abstinence or reducing alcohol consumption; 3) Using ALDH2 polymorphism as a prognostic indicator for alcohol-related cancers; 4) Targeting ALDH2 for chemoprevention; and 5) Setting guidelines for alcohol consumption among ALDH2 deficient individuals. Future studies should evaluate whether these strategies are effective for preventing the occurrence of alcohol-related cancers.

Changing relationships between smoking and psychiatric disorders across twentieth century birth cohorts: clinical and research implications.

As the risks of tobacco use become recognized and smoking becomes stigmatized, new smokers may be increasingly driven to smoke by biological or genetic vulnerabilities rather than social desirability. Given that genetic risk for deviant proneness is shared across other psychiatric and addictive disorders, we predicted that as rates of smoking decreased through the latter half of the twentieth century, associations between smoking and psychopathology would increase. Participants (N=25 412) from a large US study-the National Epidemiologic Survey on Alcohol and Related Conditions, NESARC-were interviewed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV Version (AUDADIS-IV) and classified into one of five birth cohort decades (1940s to 1980s) and three smoking history (nonsmokers, never-dependent smokers and ever-dependent smokers) groups. We found that the prevalence of smoking decreased across the five birth cohorts, but associations of smoking with drug and AUDs, attention-deficit hyperactivity disorder, bipolar disorder and antisocial personality disorder, each increased monotonically in more recently born cohorts, even after adjusting for concurrent demographic and socioeconomic changes. For drug and AUDs, increases were observed among smokers both with and without a history of nicotine dependence; for other outcomes, increases were entirely driven by nicotine-dependent smokers. Findings suggest that smokers in more recent cohorts have disproportionately high psychiatric vulnerability, and may benefit from greater mental health screenings. Differentiating between casual and dependent smokers may further help prioritize those at greatest risk. Researchers should also be aware of potential variation in psychiatric comorbidity based on cohort of birth when defining groups of smokers, to minimize confounding.

Validating Harmful Alcohol Use as a Phenotype for Genetic Discovery Using Phosphatidylethanol and a Polymorphism in ADH1B.

BACKGROUND: Although alcohol risk is heritable, few genetic risk variants have been identified. Longitudinal electronic health record (EHR) data offer a largely untapped source of phenotypic information for genetic studies, but EHR-derived phenotypes for harmful alcohol exposure have yet to be validated. Using a variant of known effect, we used EHR data to develop and validate a phenotype for harmful alcohol exposure that can be used to identify unknown genetic variants in large samples. Herein, we consider the validity of 3 approaches using the 3-item Alcohol Use Disorders Identification Test consumption measure (AUDIT-C) as a phenotype for harmful alcohol exposure. METHODS: First, using longitudinal AUDIT-C data from the Veterans Aging Cohort Biomarker Study Cohort (VACS-BC), we compared 3 metrics of AUDIT-C using correlation coefficients: (i) AUDIT-C closest to blood sampling (closest AUDIT-C), (ii) the highest value (highest AUDIT-C), (iii) and longitudinal trajectories generated using joint trajectory modeling (AUDIT-C trajectory). Second, we compared the associations of the 3 AUDIT-C metrics with phosphatidylethanol (PEth), a direct, quantitative biomarker for alcohol in the overall sample using chi-square tests for trend. Last, in the subsample of African Americans (AAs; n = 1,503), we compared the associations of the 3 AUDIT-C metrics with rs2066702 a common missense (Arg369Cys) polymorphism of the ADH1B gene, which encodes an alcohol dehydrogenase isozyme. RESULTS: The sample (n = 1,851, 94.5% male, 65% HIV+, mean age 52 years) had a median of 7 AUDIT-C scores over a median of 6.1 years. Highest AUDIT-C and AUDIT-C trajectory were correlated r = 0.86. The closest AUDIT-C was obtained a median of 2.26 years after the VACS-BC blood draw. Overall and among AAs, all 3 AUDIT-C metrics were associated with PEth (all p < 0.05), but the gradient was steepest with AUDIT-C trajectory. Among AAs (36% with the protective ADH1B allele), the association of rs2066702 with AUDIT-C trajectory and highest AUDIT-C was statistically significant (p < 0.05), and the gradient was steeper for the AUDIT-C trajectory than for the highest AUDIT-C. The closest AUDIT-C was not statistically significantly associated with rs2066702. CONCLUSIONS: EHR data can be used to identify complex phenotypes such as harmful alcohol use. The validity of the phenotype may be enhanced through the use of longitudinal trajectories.

Conclusion: Special issue on genetic and alcohol use disorder research with diverse racial/ethnic groups: Key findings and potential next steps.

BACKGROUND AND OBJECTIVES: This special issue brings together papers focusing on a wide range of topics relevant to the research and understanding of the role of race/ethnicity and genetic variation for the susceptibility of developing an alcohol use disorder (AUD). METHODS: The key findings from the issue's 10 articles are reviewed and organized here around three topics: I: addictive behaviors and potential environmental influences; II: a focus on four racial/ethnic groups; and III: special methodologies. RESULTS: Several potential next steps in improving effective research strategies are highlighted: (1) implementing best practices for outreach and community engagement may reduce reluctance to participate; (2) recruiting adequately sized and racially/ethnically diverse samples will require new collaborations with investigators who successfully work in diverse communities; (3) identifying and assessing environmental influences that are both unique to, and common among, racial/ethnic groups may inform preventions for AUD; (4) use of standardized measures will facilitate the generation of larger samples and meta-analysis of research findings; and (5) use of better analytic approaches and experimental methods will improve replication in gene finding research and help advance new areas of research. CONCLUSIONS: Genetic research of AUD in diverse racial/ethnic populations is advancing. The articles in this issue examined the general theme of including diverse population groups in genetic studies and offered potential strategies for addressing some common problems. SCIENTIFIC SIGNIFICANCE: Greater inclusion of diverse racial/ethnic populations in this research is important to ensure that the benefits of new knowledge and technology are equally shared. (Am J Addict 2017;26:532-537).