Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2 , 3 and etiologically related 4 , 5 behaviors that have been resistant to gene discovery efforts 6 – 11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

Re-parameterized regression models may enable tests of crucial theoretical predictions involving interactive effects of predictors that cannot be tested directly using standard approaches. First, we present a re-parameterized regression model for the linear X linear interaction of two quantitative predictors that yields point and interval estimates of one key parameter – the cross-over point of predicted values – and leaves certain other parameters unchanged. We explain how resulting parameter estimates provide direct evidence for distinguishing ordinal from disordinal interactions. We generalize the re-parameterized model to linear X qualitative interactions, where the qualitative variable may have two or three categories, and then describe how to modify the re-parameterized model to test moderating effects. To illustrate our new approach, we fit alternate models to social skills data on 438 participants in the NICHD Study of Early Child Care. The re-parameterized regression model had point and interval estimates of the cross-over point that fell near the mean on the continuous environment measure. The disordinal form of the interaction supported one theoretical model – differential susceptibility – over a competing model that predicted an ordinal interaction.

Comorbidity among childhood disruptive behavioral disorders is commonly reported in both epidemiologic and clinical studies. These problems are also associated with early substance use and other markers of behavioral disinhibition. Previous twin research has suggested that much of the covariation between antisocial behavior and alcohol dependence is due to common genetic influences. Similar results have been reported for conduct problems and hyperactivity. For the present study, an adolescent sample consisting of 172 MZ and 162 DZ twin pairs, recruited through the Colorado Twin Registry and the Colorado Longitudinal Twin Study were assessed using standardized psychiatric interviews and personality assessments. DSM-IV symptom counts for conduct disorder and attention deficit hyperactivity disorder, along with a measure of substance experimentation and novelty seeking, were used as indices of a latent behavioral disinhibition trait. A confirmatory factor model fit to individual-level data showed a strong common factor accounting for 16-42% of the observed variance in each measure. A common pathway model evaluating the genetic and environmental architecture of the latent phenotype suggested that behavioral disinhibition is highly heritable (a(2) = 0.84), and is not influenced significantly by shared environmental factors. A residual correlation between conduct disorder and substance experimentation was explained by shared environmental effects, and a residual correlation between attention deficit hyperactivity disorder and novelty seeking was accounted for by genetic dominance. These results suggest that a variety of adolescent problem behaviors may share a common underlying genetic risk.

Background:We conducted a sibling/twin/adoption study of substance initiation, use, and problem use, estimating the relative contribution of genetic and environmental influences on these phenotypes in adolescents. Methods:The participants were 345 monozygotic twin pairs, 337 dizygotic twin pairs, 306 biological sibling pairs, and 74 adoptive sibling pairs assessed by the Colorado Center for the Genetics and Treatment of Antisocial Drug Dependence, Denver and Boulder. The initiation, use, and problem use of tobacco, alcohol, marijuana, and other illicit drugs were assessed. Tetrachoric correlations were computed for each group, and univariate model-fitting analyses were conducted.Results: There were moderate to substantial genetic influences, with the exception of alcohol use and any drug use, and modest to moderate shared environmental influences on substance initiation, use, and problem use. For alcohol and any drug, heritability was higher and the magnitude of shared environmental influences was lower for