COVID-19 outcomes among patients with dementia and age-matched controls who were hospitalized in 21 US health-care systems.

INTRODUCTION: COVID-19 had devastating impacts worldwide. However, most research examining the impact of dementia on COVID-19 outcomes has been conducted in Europe and Asia and has not examined dementia subtypes. METHODS: A retrospective analysis of electronic health record data from 21 US health-care systems examined relationships of all-cause dementia, Alzheimer's disease (AD), and vascular dementia with in-hospital mortality, intensive care unit (ICU) admission, and hospital stay duration. RESULTS: All-cause dementia, but not AD or vascular dementia independently, was associated with increased mortality risk, the inclusion of discharge to hospice as a mortality equivalent increased risk for mortality for all-cause dementia, and AD and vascular dementia. Patients with all-cause dementia and AD were less likely to be admitted to the ICU than patients without. Patients with any form of dementia had longer hospital stays than patients without. DISCUSSION: Dementia was associated with increased mortality or hospice discharge, decreased ICU admissions, and longer hospital stays. HIGHLIGHTS: Only all-cause dementia was associated with increased mortality risk. This risk was lower than what has been published in previous research. Combining mortality and hospice discharge increased risk for all dementia subtypes. All-cause and Alzheimer's disease (AD) dementia were associated with decreased intensive care unit admissions. All-cause, vascular, and AD dementia were associated with longer hospital stays.

Factors associated with 60-day readmission among inpatients with COVID-19 at 21 United States health systems.

Identifying patients at risk for readmission after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could facilitate care planning and prevention. This retrospective cohort study of 60-day readmission included 105 543 COVID-19 patients at 21 US healthcare systems who were discharged alive between February 2020 and November 2021. Generalized linear mixed regression analyses tested predictors of 60-day readmission and severity. The all-cause readmission rate was 15% (95% confidence interval [CI] = 10%-21%), with 22% (95% CI = 18%-26%) of readmitted patients needing intensive care, and 6% (95% CI = 05%-07%) dying. Factors associated with readmission included male sex, government insurance, positive smoking history, co-morbidity burden, longer index admissions, and diagnoses at index admission (e.g., cancer, chronic kidney disease, and liver disease). Death and intensive care rates at readmission declined postvaccine availability. Receiving at least two COVID-19 vaccine doses, which were more common among older patients and those with comorbid conditions, was not independently associated with readmission but predicted a reduced risk of death at readmission. This retrospective cohort study identified factors associated with all-cause readmission for patients re-admitted to the same health system after hospitalization with SARS-CoV-2 infection. Patients who are male, who smoke, who have a higher comorbidity burden, and have government insurance may benefit from additional postacute care planning.

Specificity in genetic and environmental risk for prescription opioid misuse and heroin use.

BACKGROUND: Many studies aggregate prescription opioid misuse (POM) and heroin use into a single phenotype, but emerging evidence suggests that their genetic and environmental influences may be partially distinct. METHODS: In total, 7164 individual twins (84.12% complete pairs; 59.81% female; mean age = 30.58 years) from the Australian Twin Registry reported their lifetime misuse of prescription opioids, stimulants, and sedatives, and lifetime use of heroin, cannabis, cocaine/crack, illicit stimulants, hallucinogens, inhalants, solvents, and dissociatives via telephone interview. Independent pathway models (IPMs) and common pathway models (CPMs) partitioned the variance of drug use phenotypes into general and drug-specific genetic (a), common environmental (c), and unique environmental factors (e). RESULTS: An IPM with one general a and one general e factor and a one-factor CPM provided comparable fit to the data. General factors accounted for 55% (a = 14%, e = 41%) and 79% (a = 64%, e = 15%) of the respective variation in POM and heroin use in the IPM, and 25% (a = 12%, c = 8%, e = 5%) and 80% (a = 38%, c = 27%, e = 15%) of the respective variation in POM and heroin use in the CPM. Across both models, POM emerged with substantial drug-specific genetic influence (26-39% of total phenotypic variance; 69-74% of genetic variance); heroin use did not (0% of total phenotypic variance; 0% of genetic variance in both models). Prescription sedative misuse also demonstrated significant drug-specific genetic variance. CONCLUSIONS: Genetic variation in POM, but not heroin use, is predominantly drug-specific. Misuse of prescription medications that reduce experiences of subjective distress may be partially influenced by sources of genetic variation separate from illicit drug use.

Disordered gambling in a longitudinal birth cohort: from childhood precursors to adult life outcomes.

BACKGROUND: Despite its introduction into the diagnostic nomenclature over four decades ago, there remain large knowledge gaps about disordered gambling. The primary aims of the present study were to document the long-term course, childhood precursors, and adult life outcomes associated with disordered gambling. METHODS: Participants enrolled in the population-representative Dunedin Study were prospectively followed from birth through age 45. Disordered gambling was assessed six times from age 18; composite measures of childhood social class, general intelligence, and low self-control were based on assessments obtained from birth through age 15; adult socioeconomic, financial, and legal outcomes were obtained through age 45. Lifetime disordered gambling was predicted from the three childhood precursors and the adult outcomes were predicted from lifetime disordered gambling. RESULTS: Past-year disordered gambling usually occurred at only a single time point and recurrence was relatively uncommon. Lower childhood social class, general intelligence, and self-control significantly predicted lifetime disordered gambling in adulthood. In turn, lifetime disordered gambling in adulthood significantly predicted occupational, educational, and financial problems in adulthood (ds = 0.23-0.41). These associations were markedly reduced and sometimes rendered nonsignificant after adjusting for childhood precursors (ds = 0.04-0.32). CONCLUSIONS: Socioeconomic, financial, and legal outcomes in adulthood are not merely consequences of disordered gambling, but also are predicted from childhood precursors. Deflecting the trajectories of young people at risk for developing disordered gambling may help to ameliorate not just the development of later disordered gambling, but also other associated adverse outcomes.

Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.

INTRODUCTION: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. METHODS: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. RESULTS: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97). CONCLUSIONS: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. IMPLICATIONS: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

Childhood maltreatment and disordered gambling in adulthood: disentangling causal and familial influences.

BACKGROUND: Despite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG. METHODS: Participants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates. RESULTS: Neither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality. CONCLUSIONS: These findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.

Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants.

BACKGROUND: Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue. METHODS: A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types. RESULTS: Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use. CONCLUSIONS: Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.

Educational Attainment Polygenic Scores: Examining Evidence for Gene-Environment Interplay with Adolescent Alcohol, Tobacco and Cannabis Use.

Genes associated with educational attainment may be related to or interact with adolescent alcohol, tobacco and cannabis use. Potential gene-environment interplay between educational attainment polygenic scores (EA-PGS) and adolescent alcohol, tobacco, and cannabis use was evaluated with a series of regression models fitted to data from a sample of 1871 adult Australian twins. All models controlled for age, age2, cohort, sex and genetic ancestry as fixed effects, and a genetic relatedness matrix was included as a random effect. Although there was no evidence that adolescent alcohol, tobacco or cannabis use interacted with EA-PGS to influence educational attainment, there was a significant, positive gene-environment correlation with adolescent alcohol use at all PGS thresholds (ps <.02). Higher EA-PGS were associated with an increased likelihood of using alcohol as an adolescent (ΔR2 ranged from 0.5% to 1.1%). The positive gene-environment correlation suggests a complex relationship between educational attainment and alcohol use that is due to common genetic factors.

Effects of alcohol sensitivity on alcohol-induced blackouts and passing out: An examination of the alcohol sensitivity questionnaire among underage drinkers.

BACKGROUND: The role of alcohol sensitivity in the experience of blacking out and passing out has not been well established. Here, we examined the relation between individual differences in alcohol sensitivity (i.e., numbers of drinks required to experience various effects of alcohol) and reports of blacking out and passing out in the past year. METHODS: Participants (925 healthy, underage college student drinkers) completed the Alcohol Sensitivity Questionnaire (ASQ) and reported on their past year blacking out and passing out experiences. RESULTS: The fit of the ASQ's 2-factor structure was fair (CFI = 0.90, RMSEA = 0.09) in this sample of underage drinkers. In unadjusted models, higher ASQ scores (i.e., requiring more drinks to experience effects, indicating lower alcohol sensitivity) were associated with experiencing more blackouts (IRR = 1.68 [1.31-2.15]) and passing out (IRR = 2.25 [1.59-3.18]) in the past year. After controlling for typical consumption, however, higher ASQ scores were associated with fewer past-year blackouts (IRR = 0.76 [0.60-0.98]). Total ASQ scores moderated the relationship between typical alcohol consumption and blackout occurrence (interaction IRR = 0.96 [0.93-0.98]), but not passing out occurrence (interaction IRR = 0.95 [0.89-1.01]), with the quantity of alcohol consumed more strongly associated with blackout occurrence among higher-sensitivity than lower-sensitivity drinkers. CONCLUSIONS: These findings are consistent with prior work suggesting that low sensitivity may act as a paradoxical risk factor for certain heavy drinking effects, contributing to higher levels of alcohol consumption and more frequent negative consequences while also conferring protection (relative to high-sensitivity peers) at a given level of alcohol exposure.

High-Intensity Drinking in Adult Australian Twins.

BACKGROUND: Many adult drinkers consume far beyond the binge threshold. This "high-intensity drinking" (HID), defined as 2 (HID-2) and 3 (HID-3) times the binge threshold, is of public health interest due to its role in acute alcohol-related harms. Research on HID has mostly been limited to college-aged young adults, focused on contextual factors, and neglected the potential role of genetic influences on the propensity to engage in HID. METHODS: Structured diagnostic interviews assessing past-year alcohol involvement were conducted with 3,785 individuals (1,365 men, 2,420 women; Mage  = 32, range = 21 to 46), including 3,314 twins and 471 nontwin siblings from the Australian Twin Registry. Multinomial logistic regression analyses were conducted to compare HID-2 and HID-3 to binge drinking on demographic correlates, drinking characteristics, and drinking-related consequences. Biometric modeling was conducted to estimate the role of genetic, common, and individual-specific environmental factors in HID propensity. RESULTS: Among past-year drinkers, the prevalence of HID-2 and HID-3 was both 22%, with men disproportionally represented. The frequencies of drinking, intoxication, and binge drinking significantly increased across the heavier drinking categories, which also evidenced higher average consumption quantities and higher rates of alcohol-related consequences. The propensity to engage in HID was significantly heritable (A = 37% [95% CI: 28 to 46%]), with individual-specific environmental influences accounting for the remainder of the variance. CONCLUSIONS: This study convincingly demonstrates that HID is not restricted to college-aged young adults, but also can be highly prevalent among those of working age, and that the propensity to engage in HID is partially explained by genetic influences.

Contributions of Nicholas Martin to Gambling Disorder Research.

Professor Nicholas G. Martin, from QIMR Berghofer Medical Research Institute in Brisbane, Australia, is a world leader in the effort to understand the genetic architecture underlying disordered gambling. This article pays tribute to Nick and his almost two decades of gambling research, highlighting his many strengths, ranging from the use of ingenious recruitment approaches, twin study methods, genomewide association studies, to facilitating international collaborations.

Neighborhood alcohol outlet density and genetic influences on alcohol use: evidence for gene-environment interaction.

BACKGROUND: Genetic influences on alcohol involvement are likely to vary as a function of the 'alcohol environment,' given that exposure to alcohol is a necessary precondition for genetic risk to be expressed. However, few gene-environment interaction studies of alcohol involvement have focused on characteristics of the community-level alcohol environment. The goal of this study was to examine whether living in a community with more alcohol outlets would facilitate the expression of the genetic propensity to drink in a genetically-informed national survey of United States young adults. METHODS: The participants were 2434 18-26-year-old twin, full-, and half-sibling pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. Participants completed in-home interviews in which alcohol use was assessed. Alcohol outlet densities were extracted from state-level liquor license databases aggregated at the census tract level to derive the density of outlets. RESULTS: There was evidence that the estimates of genetic and environmental influences on alcohol use varied as a function of the density of alcohol outlets in the community. For example, the heritability of the frequency of alcohol use for those residing in a neighborhood with ten or more outlets was 74% (95% confidence limits = 55-94%), compared with 16% (95% confidence limits = 0-34%) for those in a neighborhood with zero outlets. This moderating effect of alcohol outlet density was not explained by the state of residence, population density, or neighborhood sociodemographic characteristics. CONCLUSIONS: The results suggest that living in a neighborhood with many alcohol outlets may be especially high-risk for those individuals who are genetically predisposed to frequently drink.

Genetic and environmental influences on gambling disorder liability: a replication and combined analysis of two twin studies.

BACKGROUND: Gambling disorder (GD), recognized in Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) as a behavioral addiction, is associated with a range of adverse outcomes. However, there has been little research on the genetic and environmental influences on the development of this disorder. This study reports results from the largest twin study of GD conducted to date. METHODS: Replication and combined analyses were based on samples of 3292 (mean age 31.8, born 1972-79) and 4764 (mean age 37.7, born 1964-71) male, female, and unlike-sex twin pairs from the Australian Twin Registry. Univariate biometric twin models estimated the proportion of variation in the latent GD liability that could be attributed to genetic, shared environmental, and unique environmental factors, and whether these differed quantitatively or qualitatively for men and women. RESULTS: In the replication study, when using a lower GD threshold, there was evidence for significant genetic (60%; 95% confidence interval (CI) 45-76%) and unique environmental (40%; 95% CI 24-56%), but not shared environmental contributions (0%; 95% CI 0-0%) to GD liability; this did not significantly differ from the original study. In the combined analysis, higher GD thresholds (such as one consistent with DSM-5 GD) and a multiple threshold definitions of GD yielded similar results. There was no evidence for quantitative or qualitative sex differences in the liability for GD. CONCLUSIONS: Twin studies of GD are few in number but they tell a remarkably similar story: substantial genetic and unique environmental influences, with no evidence for shared environmental contributions or sex differences in GD liability.

Genetic Epidemiology of Liability for Alcohol-Induced Blacking and Passing Out.

BACKGROUND: Individuals differ in their sensitivity to alcohol's physiological effects, including blacking and passing out. Blackouts are periods of impaired memory formation when an individual engages in activities they later cannot recall, while passing out results in loss of consciousness. METHODS: The sample consisted of 3,292 adult twins from the Australian Twin Registry. Univariate twin analyses were conducted to examine the contributions of genetic and environmental influences to blacking and passing out occurrence and susceptibility (accounting for frequency of intoxication). Evidence for shared etiology of susceptibility to blacking and passing out was examined using bivariate twin analyses. RESULTS: Although blacking and passing out were strongly associated (odds ratio (OR) = 4.45, 95% confidence interval (CI): [3.85, 5.14]), the genetic epidemiology was quite different. Genetic (43%) and nonshared environmental (57%) influences contributed to liability for blackout occurrence. For passing out occurrence, there was evidence of sex differences. Among men, genetic (32%) and nonshared environmental (68%) influences contributed, whereas among women, there were shared (29%) and nonshared environmental (72%) influences. After accounting for frequency of intoxication, genetic influences on blackout susceptibility remained significant; in contrast, only nonshared environmental influences were significant for passing out susceptibility. There was evidence for overlapping genetic and nonshared environmental factors influencing susceptibility to blacking and passing out among men; among women, there were overlapping nonshared environmental influences. CONCLUSIONS: Blacking and passing out are 2 common sedative-like effects of heavy drinking, and people differ considerably in their susceptibility to these effects. This study suggests that differences in blackout susceptibility can be explained by genetic factors in both men and women, while differences in susceptibility to pass out after consuming alcohol may be attributable to environmental influences, particularly among women. These environmental factors may include changing social and cultural norms about alcohol use, drinking context, and the type(s) of alcohol consumed.

Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling.

Disordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

Intensity of Daily Drinking and Its Relation to Alcohol Use Disorders.

BACKGROUND: Daily drinking is an important public health concern and informative for evaluating diagnostic classification. In particular, daily binge drinkers might be considered as the prototype of some forms of alcoholism, as this drinking pattern may drive many alcohol use disorder (AUD) symptoms. However, daily drinking potentially captures a wide range of drinkers, including light-moderate daily drinkers who exhibit presumed control over their drinking behavior and might benefit from salutary effects on health. This study examined the heterogeneity of daily drinkers in detail. METHODS: Data from the 2 waves of the National Epidemiologic Survey on Alcohol and Related Conditions were used. Participants who reported drinking "every day" during the last 12 months were classified as daily drinkers. A series of regression and logistic regression analyses were conducted to investigate the association between daily drinking and various outcomes. RESULTS: Daily drinkers were found to vary considerably from each other with respect to diagnostic status, level of consumption, demographic composition, and a range of drinking and health correlates. Further, a substantial number of daily binge drinkers were not diagnosed with AUD under the DSM-IV or DSM-5, although in most groups, the DSM-5 criteria diagnosed a larger percentage of participants. CONCLUSIONS: Daily drinkers represent a highly heterogeneous group, and the correlates of daily drinking depend on the usual quantity of daily drinks and the frequency of alcohol-related problems in a given sample. Moreover, AUD, defined both according to DSM-IV and DSM-5, did not capture more than 68% of daily binge drinkers. Given that daily binge drinking is an extremely high threshold for use, this finding may present a challenge for our current classification system.

Has the Genetic Contribution to the Propensity to Gamble Increased? Evidence From National Twin Studies Conducted in 1962 and 2002.

Social changes, such as the expansion of legal forms of gambling, can influence not only the prevalence of gambling, but can also shape the relative importance of genetic and environmental contributions to individual differences in the propensity to gamble. In the present study, I examined differences in the prevalence and in the relative contribution of genetic and environmental factors to gambling involvement in the United States in 1962 versus 2002. The data came from two sources: (1) a survey of 839 17-year-old same-sex twin pairs from the National Merit Scholarship Qualifying Test twin study, and (2) an interview of 477 18- to 26-year-old same-sex twin pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. Similar measures of gambling participation were included in the two studies. Evidence for a genotype-by-time interaction was evaluated by testing whether the contribution of genetic influences was greater in the more recently born cohort of twins. Despite the major changes in the gambling landscape over the intervening 40 years, there was no evidence for such an interaction. The contribution of genetic factors and environmental factors did not significantly differ and there was no evidence for genetic influences at either time point. Instead, the variation in the propensity to gamble was explained nearly equally by common and unique environmental factors. Explanations for this surprising finding are discussed.

Moderation of Genetic Influences on Alcohol Involvement by Rural Residency among Adolescents: Results from the 1962 National Merit Twin Study.

Adolescents in rural and urban areas may experience different levels of environmental restrictions on alcohol use, with those in rural areas experiencing greater monitoring and less access to alcohol. Such restrictions may limit expression of genetic vulnerability for alcohol use, resulting in a gene-environment interaction (G × E). This phenomenon has previously been reported in Finnish and Minnesota adolescents. The current study used data from 839 same-sex twin pairs from the 1962 National Merit Scholarship Qualifying Test to determine whether the G × E interaction would be evident in this earlier time period. We also assessed whether the G × E interaction would be moderated by sex, and whether family socioeconomic status (SES; income and parental education) may mediate the G × E interaction. Findings showed the expected interaction among females, with a weaker contribution of genes (2 vs. 44%) and greater contribution of shared environment (62 vs. 29%) to variation in alcohol involvement among rural as compared to urban residents. The G × E interaction was not observed among males, and operated independently from differences in family SES among rural and urban adolescents. This study represents a partial replication in a novel setting of the moderation of the genetic contribution to alcohol use by rural/urban residency, and suggests that SES differences may not explain this effect.

Developmental Etiologies of Alcohol Use and Their Relations to Parent and Peer Influences Over Adolescence and Young Adulthood: A Genetically Informed Approach.

BACKGROUND: Distinct changes in alcohol use etiologies occur during adolescence and young adulthood. Additionally, measured environments known to influence alcohol use such as peers and parenting practice can interact or be associated with this genetic influence. However, change in genetic and environmental influences over age, as well as how associations with measured environments change over age, is understudied. METHODS: The National Longitudinal Study of Adolescent Health (Add Health) sibling subsample was used to examine data-driven biometric models of alcohol use over ages 13 to 27. Associations between friends' drinking, parental autonomy granting, and maternal closeness were also examined. RESULTS: The best-fitting model included a 5-factor model consisting of early (ages 13 to 20) and overall (ages 13 to 27) additive genetic and unique environmental factors, as well as 1 overall common environment factor. The overall additive genetic factor and the early unique environment factor explained the preponderance of mean differences in the alcohol use over this portion of the life span. The most important factors explaining variance attributed to alcohol use changed over age. Additionally, friend use had the strongest associations with genetic and environmental factors at all ages, while parenting practices had almost no associations at any age. CONCLUSIONS: These results supplement previous studies indicating changes in genetic and environmental influences in alcohol use over adolescence and adulthood. However, prior research suggesting that constraining exogenous predictors of genetic and environmental factors to have effects of the same magnitude across age overlooks the differential role of factors associated with alcohol use during adolescence. Consonant with previous research, friend use appears to have a more pervasive influence on alcohol use than parental influence during this age. Interventions and prevention programs geared toward reducing alcohol use in younger populations may benefit from focus on peer influence.

A Novel Tobacco Use Phenotype Suggests the 15q25 and 19q13 Loci May be Differentially Associated With Cigarettes per Day and Tobacco-Related Problems.

INTRODUCTION: Tobacco use is associated with variation at the 15q25 gene cluster and the cytochrome P450 (CYP) genes CYP2A6 and CYP2B6. Despite the variety of outcomes associated with these genes, few studies have adopted a data-driven approach to defining tobacco use phenotypes for genetic association analyses. We used factor analysis to generate a tobacco use measure, explored its incremental validity over a simple indicator of tobacco involvement: cigarettes per day (CPD), and tested both phenotypes in a genetic association study. METHODS: Data were from the University of California, San Francisco Family Alcoholism Study (n = 1942) and a Native American sample (n = 255). Factor analyses employed a broad array of tobacco use variables to establish the candidate phenotype. Subsequently, we conducted tests for association with variants in the nicotinic acetylcholine receptor and CYP genes. We explored associations with CPD and our measure. We then examined whether the variants most strongly associated with our measure remained associated after controlling for CPD. RESULTS: Analyses identified one factor that captured tobacco-related problems. Variants at 15q25 were significantly associated with CPD after multiple testing correction (rs938682: p = .00002, rs1051730: p = .0003, rs16969968: p = .0003). No significant associations were obtained with the tobacco use phenotype; however, suggestive associations were observed for variants in CYP2B6 near CYP2A6 (rs45482602: ps = .0082, .0075) and CYP4Z2P (rs10749865: ps = .0098, .0079). CONCLUSIONS: CPD captures variation at 15q25. Although strong conclusions cannot be drawn, these finding suggest measuring additional dimensions of problems may detect genetic variation not accounted for by smoking quantity. Replication in independent samples will help further refine phenotype definition efforts. IMPLICATIONS: Different facets of tobacco-related problems may index unique genetic risk. CPD, a simple measure of tobacco consumption, is associated with variants at the 15q25 gene cluster. Additional dimensions of tobacco problems may help to capture variation at 19q13. Results demonstrate the utility of adopting a data-driven approach to defining phenotypes for genetic association studies of tobacco involvement and provide results that can inform replication efforts.