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1.  Functional Neuroimaging Study in Identical Twin Pairs Discordant for Regular Cigarette Smoking 
Addiction biology  2012;18(1):98-108.
Despite the tremendous public health and financial burden of cigarette smoking, relatively little is understood about brain mechanisms that subserve smoking behavior. This study investigated the effect of lifetime regular smoking on brain processing in a reward guessing task using functional magnetic resonance imaging (fMRI) and a cotwin-control study design in monozygotic (MZ) twin pairs that maximally controls for genetic and family background factors. Young adult (24–34 years) MZ female twin pairs (n=15 pairs), discordant for regular smoking defined using Centers for Disease Control (CDC) criteria as having smoked ≥100 cigarettes lifetime were recruited from an ongoing genetic epidemiological longitudinal study of substance use and psychopathology. We applied hypothesis-driven region of interest and whole brain analyses to investigate the effect of regular smoking on reward processing. Reduced response to reward and punishment in regular compared to never-regular smokers was seen in hypothesis-driven region of interest analysis of bilateral ventral striatum. Whole brain analysis identified bilateral reward-processing regions that showed activation differences in response to winning or losing money but no effect of regular smoking; and frontal/parietal regions, predominantly in the right hemisphere, that showed robust effect of regular smoking but no effect of winning or losing money. Altogether, using a study design that maximally controls for group differences, we found that regular smoking had modest effects on striatal reward processing regions but robust effects on cognitive control/attentional systems.
PMCID: PMC3470739  PMID: 22340136
cigarette smoking; cotwin-control; fMRI
2.  An Australian Twin Study of Cannabis and Other Illicit Drug Use and Misuse, and Other Psychopathology 
Cannabis is the most widely used illicit drug throughout the developed world and there is consistent evidence of heritable influences on multiple stages of cannabis involvement including initiation of use and abuse/dependence. In this paper, we describe the methodology and preliminary results of a large-scale interview study of 3,824 young adult twins (born 1972–1979) and their siblings. Cannabis use was common with 75.2% of males and 64.7% of females reporting some lifetime use of cannabis while 24.5% of males and 11.8% of females reported meeting criteria for DSM-IV cannabis abuse or dependence. Rates of other drug use disorders and common psychiatric conditions were highly correlated with extent of cannabis involvement and there was consistent evidence of heritable influences across a range of cannabis phenotypes including early (≤15 years) opportunity to use (h2 = 72%), early (≤16 years) onset use (h2 = 80%), using cannabis 11+ times lifetime (h2 = 76%), and DSM abuse/dependence (h2 = 72%). Early age of onset of cannabis use was strongly associated with increased rates of subsequent use of other illicit drugs and with illicit drug abuse/dependence; further analyses indicating that some component of this association may have been mediated by increasing exposure to and opportunity to use other illicit drugs.
PMCID: PMC3717485  PMID: 22874079
Cannabis; twin; Comorbidity; Illicit drugs
3.  Meta-analysis of genome-wide association studies for personality 
Molecular psychiatry  2010;17(3):337-349.
Personality can be thought of as a set of characteristics that influence people’s thoughts, feelings, and behaviour across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in ten discovery samples (17 375 adults) and five in-silico replication samples (3 294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data were available of ~2.4M Single Nucleotide Polymorphisms (SNPs; directly typed and imputed using HAPMAP data). In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P = 2.8 × 10−8 and 3.1 × 10−8) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P = 4.9 × 10−8). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In-silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.
PMCID: PMC3785122  PMID: 21173776
Personality; Five-Factor Model; Genome-wide association; Meta-analysis; Genetic variants
4.  Genetic Influences on Developmental Smoking Trajectories 
Addiction (Abingdon, England)  2012;107(9):1696-1704.
To investigate the relative contribution of genetic and environmental factors on smoking trajectory membership and to test whether individual smoking trajectories represent phenotypic thresholds of increasing genetic risk along a common genetic liability dimension.
Prospective study of a birth cohort of female like-sex twin pairs.
Participants completed diagnostic interview surveys 4 times from adolescence (average age 16) through young adulthood (average age 25).
Female twins who had smoked ≥100 cigarettes lifetime (n=1466 regular smokers).
Number of cigarettes smoked per day during the heaviest period of smoking (2 waves) or during the past 12 months (2 waves).
A 4-trajectory class solution provided the best fit to cigarette consumption data and was characterized by Low (n=564, 38.47%), Moderate (n=366, 24.97%), and High level smokers (n=197, 13.44%), and smokers who increased their smoking from adolescence to young adulthood (n=339, 23.12%). The best genetic model fit was a 3-category model that comprised the Low, a combined Increasing + Moderate, and High trajectories. This trajectory categorization was heritable (72.7%) with no evidence for significant contribution from shared environmental factors.
The way that smoking patterns develop in adolescence has a high level of heritability.
PMCID: PMC3412932  PMID: 22385035
smoking trajectories; twins; heritability
6.  Do Early Experiences with Cannabis vary in Cigarette Smokers? 
Drug and alcohol dependence  2012;128(3):255-259.
We examine whether regular cigarette smokers were more likely to be exposed to and use cannabis at an earlier age, and further, upon initiation, whether their initial experiences with cannabis varied from those reported by never/non-regular cigarette smokers.
A sample of 3797 Australian twins and siblings aged 21–46 years was used. Survival analyses examined whether cigarette smokers were at increased likelihood of early opportunity to use cannabis and early onset of cannabis use. Logistic regression examined whether cigarette smokers reported greater enjoyment of their cannabis experience, inhaling on the first try, differing positive and negative initial subjective reactions, smoked cigarettes with cannabis the first time and were more likely to try cannabis again within a week.
Regular cigarette smokers were more likely to report an earlier opportunity to use cannabis and early onset of cannabis use. Regular cigarette smokers were also considerably more likely to have enjoyed their first experience with cannabis and reported higher rates of positive initial reactions. They were more likely to report inhaling on the first try and smoking cigarettes with cannabis. Potentially negative subjective reactions were also elevated in regular cigarette smokers. Importantly, cigarette smokers were at 1.87 increased odds of smoking cannabis within a week of their initial use.
These findings indicate that the well-known overlap in cannabis and cigarette smoking behaviors may evolve as early as opportunity to use and extend through the course of the substance use trajectory.
PMCID: PMC3614406  PMID: 23010290
cannabis; cigarette; initial reaction; onset; opportunity
7.  Examining the Association of NRXN3 SNPs with Borderline Personality Disorder Phenotypes in Heroin Dependent Cases and Socio-economically Disadvantaged Controls* 
Drug and alcohol dependence  2012;128(3):10.1016/j.drugalcdep.2012.11.011.
Borderline personality disorder (BPD) and substance use disorders frequently cooccur; their dual presence predicts poor prognosis. The genetic underpinnings of BPD have not been well-characterized and could offer insight into comorbidity. The current report focuses on the association of Neurexin 3 (NRXN3) single nucleotide polymorphisms (SNPs) with BPD symptoms in heroin dependent cases and controls.
The sample of the Comorbidity and Trauma Study, a genetic association study of heroin dependence, consists of Australian heroin dependent cases ascertained from opioid replacement therapy clinics and controls ascertained in nearby economically-disadvantaged neighborhoods. The assessment included a screening instrument for BPD, used previously in Australian population surveys. Genotypic and BPD phenotypic data were available for 1439 cases and 507 controls. We examined the association of 1430 candidate gene SNPs with BPD phenotypes.
One or more NRXN3 SNPs were nominally associated with all BPD phenotypes; however, none met the conservative significance threshold we employed to correct for multiple testing. The most strongly associated SNPs included rs10144398 with identity disturbance (p=4.9 × 10−5) and rs10151731 with affective instability (p=8.8 × 10−5). The strongest association with screening positive for BPD was found for the NRXN3 SNP, rs10083466 (p=.0013). Neither the correlation of BPD phenotypes nor the linkage disequilibrium relationships of the SNPs account for the number of observed associations involving NRXN3 SNPs.
Our findings provide intriguing preliminary evidence for the association of NRXN3 with BPD phenotypes. The strongest associations were found for traits (i.e., affective instability; identity disturbance) also observed with other disorders.
PMCID: PMC3832348  PMID: 23245376
borderline personality disorder; NRXN3; genetic association study; heroin dependence
8.  Use of a predictive model derived from in vivo endophenotype measurements to demonstrate associations with a complex locus, CYP2A6 
Human Molecular Genetics  2012;21(13):3050-3062.
This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes made comparisons by dividing subjects into broad categories based on assumptions that simplify the range of function of different CYP2A6 alleles, their numerous possible diplotype combinations and non-additive allele effects. A predictive model that translates CYP2A6 diplotype into a single continuous variable was previously derived from an in vivo metabolism experiment in 189 European Americans. Here, we apply this model to assess associations between genotype, inferred nicotine metabolism and smoking behaviors in larger samples without direct nicotine metabolism measurements. CYP2A6 genotype is not associated with nicotine dependence, as defined by the Fagerström Test of Nicotine Dependence, demonstrating that cigarettes smoked per day (CPD) and nicotine dependence have distinct genetic correlates. The predicted metric is significantly associated with CPD among African Americans and European American dependent smokers. Individual slow metabolizing genotypes are associated with lower CPD, but the predicted metric is the best predictor of CPD. Furthermore, optimizing the predictive model by including additional CYP2A6 alleles improves the fit of the model in an independent data set and provides a novel method of predicting the functional impact of alleles without direct metabolism measurements. Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms are the result of synthetic associations.
PMCID: PMC3373237  PMID: 22451501
9.  The interpretability of family history reports of alcoholism in general community samples: Findings in a Midwestern US twin birth cohort 
Although there is a long tradition in alcoholism research of using family history ratings, the interpretability of family history reports of alcoholism from general community samples has yet to be established.
Telephone interview data obtained from a large cohort of female like-sex twins (N = 3787, median age 22) and their biological parents (N = 2928, assessed at twins’ median age 15) were analyzed to determine agreement between parent self-report, parent ratings of coparent, and twin narrow (alcohol problems) versus broad (problem or excessive drinking) ratings of each parent.
In European ancestry (EA) families, high tetrachoric correlations were observed between twin and cotwin ratings of parental alcohol problems, between twin and parent ratings of coparent alcohol problems using symptom-based and single-item assessments, as well as moderately high correlations between twin and both mother and father self-reports. In African American (AA) families, inter-rater agreement was substantially lower than for EA families, with no cases where father ratings of maternal alcohol problems agreed with either twin ratings or mother self-report; and both cotwin agreement and mother-twin agreement were reduced. Differences between EA and AA families were not explained by differences in years of cohabitation with father or mother’s education; however, underreporting of problems by AA parents may have contributed.
Results support the use of family history ratings of parental alcoholism in general community surveys for European ancestry families, but suggest that family history assessment in African American families requires improved methods.
PMCID: PMC3330191  PMID: 22235921
alcoholism; family history assessment; community samples
10.  Suicidal Behavior, Smoking, and Familial Vulnerability 
Nicotine & Tobacco Research  2011;14(4):415-424.
Smoking is a well-established correlate of suicidal behavior. It is not known if familial risk factors contribute to this association.
Data were obtained via semistructured interviews with 1,107 twin fathers, 1,919 offspring between ages 12–32 years, and 1,023 mothers. Familial vulnerability to nicotine dependence and suicidal behavior was modeled via father and maternal self-report of these behaviors. Multinomial logistic regression models were computed with and without familial risk factors to estimate the association between offspring ever smoking, regular smoking, nicotine dependence, and a 4-level offspring suicide variable: (a) none, (b) ideation, (c) ideation + plan, and (d) ideation + plan + attempt or ideation + attempt. All models were stratified by gender and adjusted for sociodemographics, familial risk factors including parental suicidal behavior, nicotine dependence, and conduct disorder, and offspring conduct disorder, depression, alcohol abuse/dependence, and illicit drug abuse/dependence.
After adjusting for covariates and familial risk factors, ever smoking was not significantly associated with suicidal behavior in males and females. In males, regular smoking was associated with ideation + plan (odds ratio [OR] = 5.47; 95% CI: 1.05–28.60), and in females, regular smoking was associated with ideation + plan + attempt or ideation + attempt. In both genders, nicotine-dependent smoking was associated with ideation + plan + attempt or ideation + attempt (males: OR = 6.59; 95% CI: 1.91–22.70, females: OR = 3.37; 95% CI: 1.25–9.04). Comparison of models with and without familial risk factors indicated that there is no mediation of smoking status and suicidal behavior by familial risk.
Smoking and nicotine dependence are correlated with suicidal behaviour. Contributions from familial risk factors did not significantly alter this association.
PMCID: PMC3313784  PMID: 22080587
11.  Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits 
Nature genetics  2012;44(4):369-S3.
We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.
PMCID: PMC3593158  PMID: 22426310
12.  Do shared etiological factors contribute to the relationship between sexual orientation and depression? 
Psychological medicine  2011;42(3):521-532.
Gays, lesbians, and bisexuals (i.e. nonheterosexuals) have been found to be at much greater risk for many psychiatric symptoms and disorders, including depression. This may be due in part to prejudice and discrimination experienced by nonheterosexuals, but studies controlling for minority stress, or performed in very socially liberal countries, suggest that other mechanisms must also play a role. Here we test the viability of common cause (shared genetic or environmental etiology) explanations of elevated depression rates in nonheterosexuals.
A community-based sample of adult twins (N=9884 individuals) completed surveys investigating the genetics of psychiatric disorder, and were also asked about their sexual orientation. Large subsets of the sample were asked about adverse childhood experiences such as sexual abuse, physical abuse, and risky family environment, and also about number of older brothers, paternal and maternal age, and number of close friends. Data were analysed using the classical twin design.
Nonheterosexual males and females had higher rates of lifetime depression than their heterosexual counterparts. Genetic factors accounted for 31% and 44% of variation in sexual orientation and depression, respectively. Bivariate analysis revealed that genetic factors accounted for a majority (60%) of the correlation between sexual orientation and depression. In addition, childhood sexual abuse and risky family environment were significant predictors of both sexual orientation and depression, further contributing to their correlation.
Nonheterosexual men and women had elevated rates of lifetime depression, partly due to shared etiological factors, although causality cannot be definitively resolved.
PMCID: PMC3594769  PMID: 21867592
sexual orientation; childhood abuse; depression; twins; genetics
13.  Common Heritable Contributions to Low-Risk Trauma, High-Risk Trauma, Posttraumatic Stress Disorder, and Major Depression 
Archives of general psychiatry  2012;69(3):293-299.
Understanding the relative contributions of genetic and environmental factors to trauma exposure, post-traumatic stress disorder (PTSD), and major depressive disorder (MDD) is critical to developing etiologic models of these conditions and their co-occurrence.
To quantify heritable influences on low-risk trauma, high-risk trauma, PTSD, and MDD and to estimate the degree of overlap between genetic and environmental sources of variance in these 4 phenotypes.
Adult twins and their siblings were ascertained from a large population-based sample of female and male twin pairs on the basis of screening items for childhood sexual abuse and physical abuse obtained in a previous assessment of this cohort.
Structured psychiatric telephone interviews.
Total sample size of 2591: 996 female and 536 male twins; 625 female and 434 male nontwin siblings.
Main Outcome Measure
Lifetime low- and high-risk trauma exposure, PTSD, and MDD.
In the best-fitting genetic model, 47% of the variance in low-risk trauma exposure and 60% of the variance in high-risk trauma exposure was attributable to additive genetic factors. Heritable influences accounted for 46% of the variance in PTSD and 27% of the variance in MDD. An extremely high degree of genetic overlap was observed between high-risk trauma exposure and both PTSD (r =0.89; 95% CI, 0.78-0.99) and MDD (r =0.89; 95% CI, 0.77-0.98). Complete correlation of genetic factors contributing to PTSD and to MDD (r=1.00) was observed.
The evidence suggests that almost all the heritable influences on high-risk trauma exposure, PTSD, and MDD, can be traced to the same sources; that is, genetic risk is not disorder specific. Individuals with a positive family history of either PTSD or MDD are at elevated risk for both disorders and should be closely monitored after a traumatic experience for symptoms of PTSD and MDD.
PMCID: PMC3594801  PMID: 22393221
15.  DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape 
Nature genetics  2013;45(7):10.1038/ng.2649.
Transposable element (TE) derived sequences comprise half of our genome and DNA methylome, and are presumed densely methylated and inactive. Examination of the genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues revealed unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the tissue type and their expression correlated strongly with hypomethylation of the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks including H3K4me1 and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and exhibited evidence for evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks, and have acquired tissue-specific epigenetic regulation.
PMCID: PMC3695047  PMID: 23708189
16.  Correlates of alcohol abuse/dependence in early-onset alcohol-using women 
Early-onset alcohol use is associated with increased vulnerability to subsequent alcohol abuse and dependence. However, not all early-onset alcohol users develop alcohol use disorders (AUDs). Using a sample of young women from the U.S., we identify correlates that contribute to a greater likelihood of AUDs in early-onset alcohol users.
Using interview and questionnaire data on participants of the Missouri Adolescent Female Twin Study (MOAFTS), we examine whether measures from domains including socio-demographic, pubertal development, religiosity, educational achievement, adverse life events, internalizing disorders, externalizing disorders and family history and discipline were associated with development of AUDs in 1,158 women who had their first drink of alcohol prior to age 16.
Early-onset drinkers were 3.6 times more likely to meet criteria for AUDs than later onset drinkers. While univariate analyses revealed that a host of correlates were associated with likelihood of AUDs in early-onset drinkers, multivariate analyses suggested that, even after accounting for a particularly early age of onset of drinking, those with a history of physical abuse, co-twin alcohol problems, conduct disorder, regular smoking, older peers and peer substance use were considerably more likely to meet criteria for AUDs than early onset drinkers without a lifetime history of these correlates.
The progression from first drink to AUDs is complex, and while early age at first drink is a potent risk factor, other aspects of psychopathology, family history, conduct problems and peer affiliations can exacerbate or alleviate the risk of AUDs in these young female drinkers.
PMCID: PMC3571676  PMID: 21838841
alcohol; early-onset; alcohol abuse/dependence; female
17.  Chromosome 20 Shows Linkage With DSM-IV Nicotine Dependence in Finnish Adult Smokers 
Nicotine & Tobacco Research  2011;14(2):153-160.
Chromosome 20 has previously been associated with nicotine dependence (ND) and smoking cessation. Our aim was to replicate and extend these findings.
First, a total of 759 subjects belonging to 206 Finnish families were genotyped with 18 microsatellite markers residing on chromosome 20, in order to replicate previous linkage findings. Then, the replication data were combined to an existing whole-genome linkage data resulting in a total of 1,302 genotyped subjects from 357 families. ND diagnosed by DSM-IV criteria, the Fagerström Test for Nicotine Dependence (FTND) score, and the lifetime maximum number of cigarettes smoked within a 24-hr period (MaxCigs24) were used as phenotypes in the nonparametric linkage analyses.
We replicated previously reported linkage to DSM-IV ND, with a maximum logarithm of odd (LOD) score of 3.8 on 20p11, with females contributing more (maximum LOD [MLOD] score 3.4 on 20q11) than males (MLOD score 2.6 on 20p11). With the combined sample, a suggestive LOD score of 2.3 was observed for DSM-IV ND on 20p11. Sex-specific analyses revealed that the signal was driven by females with a maximum LOD score of 3.3 (on 20q11) versus LOD score of 1.3 in males (on 20q13) in the combined sample. No significant linkage signals were obtained for FTND or MaxCigs24.
Our results provide further evidence that chromosome 20 harbors genetic variants influencing ND in adult smokers.
PMCID: PMC3265743  PMID: 22039074
18.  Does variance in drinking motives explain the genetic overlap between personality and alcohol use disorder symptoms? A twin study of young women 
Genetic risk for alcohol dependence has been shown to overlap with genetic factors contributing to variation in dimensions of personality. Though drinking motives have been posited as important mediators of the alcohol-personality relation, the extent to which the genetic covariance between alcohol use disorder (AUD) symptoms (i.e. abuse and dependence criteria) and personality is explained by genetic factors contributing to variation in drinking motives remains unclear.
Using data from 2,904 young adult female twins, the phenotypic and genetic associations among personality dimensions (constraint [measured by the Multidimensional Personality Questionnaire; Tellegen, 1982], conscientiousness, neuroticism, and agreeableness [measured by the NEO-PI; Costa & McCrae, 1985]), internal drinking motives (enhancement and coping motives [measured by the Drinking Motive Questionnaire; Cooper, 1994]), and AUD symptoms were tested.
Significant genetic associations were found between all personality measures and AUD symptoms. Coping motives showed significant genetic overlap with AUD symptoms and most personality measures, whereas enhancement motives were not significantly heritable. Adjusting for coping motives, genetic correlations between AUD symptoms and traits of neuroticism and agreeableness were no longer statistically significant.
Findings suggest that genetic variation in drinking to cope might account for a considerable proportion of the genetic covariance between specific personality dimensions and AUD symptoms.
PMCID: PMC3204320  PMID: 21790670
behavior genetics; personality; drinking motives; alcohol use disorders
19.  A Latent Class Analysis of DSM-IV and Fagerström (FTND) Criteria for Nicotine Dependence 
Nicotine & Tobacco Research  2011;13(10):972-981.
Nicotine dependence is associated with considerable morbidity and mortality. Two predominant classification systems, the Diagnostic and Statistical Manual (DSM-IV) and Fagerström Test for Nicotine Dependence (FTND), have been used to measure liability to nicotine dependence, yet few studies have attempted to simultaneously examine both sets of criteria.
Using a sample of 624 regular smoking individuals who are offspring of Vietnam Era Twin fathers ascertained for an offspring of twin study, we applied latent class analysis to the 7 DSM-IV and the 6 FTND criteria to classify individuals by their nicotine dependence symptom profiles. Post-hoc across-class comparisons were conducted using a variety of smoking-related variables and aspects of psychopathology. Whether a single class identified offspring at high genetic and environmental vulnerability was also investigated.
The cross-diagnosis kappa was .30. A 4-class solution fit these data best. The classes included a low DSM-low FTND class and a high DSM-high FTND class; a moderate DSM-moderate FTND class, which was distinguished by moderate levels of smoking and intermediate levels of comorbid psychopathology; and a light smoking–moderate FTND class consisting primarily of lighter smokers with a more recent onset of regular smoking. High genetic and environmental vulnerability to nicotine dependence was noted in all classes with no statistically significant across-class differences.
In general, the DSM-IV and FTND criteria performed similarly to define a continuum of risk for nicotine dependence. The emerging class of light smokers should be further investigated to assess whether they transition to another class or remain as such.
PMCID: PMC3179671  PMID: 21778154
20.  The Relationship Between rs3779084 in the Dopa Decarboxylase (DDC) Gene and Alcohol Consumption is Mediated by Drinking Motives in Regular Smokers 
Motivational models of alcohol use propose that the motivation to consume alcohol is the final common pathway to its use. Both alcohol consumption and drinking motives are influenced by latent genetic factors that partially overlap. This study investigated whether drinking motives mediate the associations between alcohol consumption and 2 single-nucleotide polymorphisms (SNPs) from genes involved in serotonin (TPH2; rs1386496) and dopamine synthesis (DDC; rs3779084). Based on earlier work showing that enhancement and coping motives were heritable in regular smokers but not in nonregular smokers, we hypothesized these motives would mediate the relationships between alcohol consumption and these SNPs in regular smokers.
Drinking motives data were available from 830 young adult female twins (n = 344 regular smokers and n = 486 never/nonregular smokers). We used confirmatory factor analyses to model enhancement, coping, and alcohol consumption factors and to conduct mediation analyses in the regular smoker and never/nonregular smoker groups.
Our hypothesis was partially supported. The relationship between alcohol consumption and rs1386496 was not mediated by drinking motives in either group. However, in the regular smokers, the relationship between alcohol consumption and rs3779084 was mediated by enhancement and coping motives. Carriers of the rs3779084 minor allele who were regular smokers reported more motivation to consume alcohol. Given this pattern of results was absent in the never/nonregular smokers, our results are consistent with a gene × smoking status interaction.
In regular smokers, variability at the locus marked by rs3779084 in the DDC gene appears to index biologically based individual differences in the motivation to consume alcohol to attain or improve a positive affective state or to relieve a negative one. These results could be because of increased sensitivity to the reinforcing effects of alcohol among minor allele carriers who smoke, which might be due to structural or functional differences in mesorticolimic dopamine “reward” circuitry.
PMCID: PMC3433798  PMID: 21797889
Alcohol; Tobacco; Drinking Motives; DDC; TPH2; Mediation
22.  Smoking Outcome Expectancies in Young Adult Female Smokers: Individual Differences and Associations with Nicotine Dependence in a Genetically-informative Sample 
Drug and alcohol dependence  2010;116(1-3):37-44.
Outcome expectancy is a central construct in models of addiction. Several outcome expectancies associated with smoking cigarettes have been identified, and studies suggest that individual differences in smoking expectancies are related to important aspects of tobacco use, including levels of smoking, nicotine dependence and smoking cessation. In the present study, we used a novel analytic method, exploratory structural equation modeling (ESEM), to quantify smoking expectancies from a subset of items adapted from the Smoking Consequences Questionnaire (SCQ; Brandon and Baker, 1991) and SCQ-Adult (Copeland et al., 1995). In our sample of 1262 monozygotic and dizygotic young adult, female twins who were regular smokers, we quantified six smoking expectancy factors similar to those reported in previous studies. These included Negative Affect Reduction, Boredom Reduction, Weight Control, Taste Manipulation, Craving/Addiction and Stimulation-State Enhancement. We used genetic model-fitting to examine the extent to which individual differences in the expectancies were influenced by latent genetic, shared environmental and non-shared environmental factors. We also examined the validity of the expectancy factors by examining their associations with nicotine dependence (ND) before and after adjusting for comorbid diagnoses of drug dependence and alcohol use disorder. Results of the validity analysis indicated that all of the expectancies were associated with ND after covariate adjustment. Although we lacked the statistical power to distinguish between genetic and shared environmental sources of variance, our results suggest that smoking outcome expectancies aggregate in families, but the majority of variance in these expectancies is due to environmental factors specific to the individual.
PMCID: PMC3105190  PMID: 21194853
Smoking expectancies; Smoking Consequences Questionnaire; Nicotine Dependence; Genetics; Female
23.  Evidence of Differential Allelic Effects between Adolescents and Adults for Plasma High-Density Lipoprotein 
PLoS ONE  2012;7(4):e35605.
A recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25–30% of heritability for each trait. Little is known about how these loci affect lipid levels in early life, but there is evidence that genetic effects on HDL- and LDL-cholesterol (HDL-C, LDL-C) and triglycerides vary with age. We studied Australian adults (N = 10,151) and adolescents (N = 2,363) who participated in twin and family studies and for whom we have lipid phenotypes and genotype information for 91 of the 95 genetic variants. Heterogeneity tests between effect sizes in adult and adolescent cohorts showed an excess of heterogeneity for HDL-C (pHet<0.05 at 5 out of 37 loci), but no more than expected by chance for LDL-C (1 out of 14 loci), or trigycerides (0 out 24). There were 2 (out of 5) with opposite direction of effect in adolescents compared to adults for HDL-C, but none for LDL-C. The biggest difference in effect size was for LDL-C at rs6511720 near LDLR, adolescents (0.021±0.033 mmol/L) and adults (0.157±0.023 mmol/L), pHet = 0.013; followed by ZNF664 (pHet = 0.018) and PABPC4 (pHet = 0.034) for HDL-C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults.
PMCID: PMC3329456  PMID: 22530058
24.  Alcoholic Marriage: Later Start, Sooner End 
Although associations between drinking behavior and marital status are well documented, timing of marital transitions as a function of alcohol use or disorder has received limited empirical attention.
We examine the relationship between lifetime history of alcohol dependence (AD) and timing and survival of first marriages in a sample of 3575 female and 1845 male adult Australian twins born mostly between 1940 and 1964. Survival analyses were conducted using Cox proportional hazards regression models.
Results indicate moderate delays in marriage associated with AD for both women and men. Among ever married respondents, AD was strongly predictive of early separation, with similar effects observed for women and men. Heritable sources of covariation were also documented. For women, genetic influences shared between early-onset AD and marital timing were found. Genetic influences shared between AD and marital survival were observed for women without regard to onset and for men with later-onset AD.
Results confirm the importance of AD as a predictor of both timing and survival of first marriages, with genetic influences contributing to observed associations.
PMCID: PMC3066284  PMID: 21244438
alcohol dependence; marital onset; marital survival; genetic risks
25.  Genome-wide association study of height and body mass index in Australian twin families 
Human height and body mass index are influenced by a large number of genes, each with small effects, along with environment. To identify common genetic variants associated with these traits, we performed genome-wide association studies in 11,536 individuals composed of Australian twins, family members, and unrelated individuals at ~550,000 genotyped SNPs. We identified a single genome-wide significant variant for height (P value = 1.06 × 10-9) located in HHIP, a well-replicated height-associated gene. Suggestive levels of association were found for other known genes associated with height (P values < 1 × 10-6): ADAMTSL3, EFEMP1, GPR126, and HMGA2; and BMI (P values < 1 × 10-4): FTO and MC4R. Together, these variants explain less than 2% of total phenotypic variation for height and 0.5% for BMI.
PMCID: PMC3232006  PMID: 20397748

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