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1.  Childhood Sexual Abuse and Early Substance Use in Adolescent Girls: The Role of Familial Influences 
Addiction (Abingdon, England)  2013;108(5):993-1000.
To assess the extent to which the association between childhood sexual abuse (CSA) and early use of alcohol, cigarettes, and cannabis in adolescent girls is mediated by risk factors that tend to cluster in families where CSA occurs.
An abridged version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered by telephone. Participants: 3,761 female twins aged 18–29 (14.6% African American, 85.4% European American).
CSA experiences and history of substance use were queried in the SSAGA-based interviews.
After controlling for familial influences on early substance use by including co-twin early use status in models, separate Cox proportional hazards regression analyses predicting onset of alcohol, cigarette, and cannabis use revealed a significant association with CSA. The effect was observed through age 19 for cigarettes and through age 21 for cannabis, but was limited to age 14 or younger for alcohol, with the most pronounced risk before age 10 (HR=4.59; CI: 1.96–10.74). CSA-associated risk for initiation of cigarette and cannabis use was also highest in the youngest age range, but the decline with age was much more gradual and the hazard ratios significantly lower (1.70; CI:1.13–2.56 for cigarettes and 2.34, CI:1.58–3.46 for cannabis).
Childhood sexual abuse history is a distinct risk factor for use of cigarettes and cannabis, and a very strong predictor of early age at first drink.
PMCID: PMC3628962  PMID: 23316725
sexual abuse; alcohol; cigarettes; cannabis; women
2.  Genome-wide Association Study of a Quantitative Disordered Gambling Trait 
Addiction biology  2012;18(3):511-522.
Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1,312 twins from 894 Australian families. Association was conducted for 2,381,914 single nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values < 1 × 10−5 with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime DSM-IV pathological gambling and SOGS classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist induced gambling in individuals with Parkinson’s disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling.
PMCID: PMC3470766  PMID: 22780124
association; disordered gambling; genomewide; MERLIN; quantitative
3.  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
4.  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
5.  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
7.  Cannabinoid receptor (CNR1) genotype moderates the effects of childhood physical abuse on anhedonia and depression 
Archives of general psychiatry  2012;69(7):732-740.
The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited.
To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and further, to replicate this interaction in an independent sample.
Genetic association study in 1041 young adult U.S. women with replication in an independent Australian sample of 1428 heroin dependent cases and 506 neighborhood controls.
Main outcome measure
Self-reported anhedonia and depression (with anhedonia).
In both samples, those who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with one or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in those reporting childhood physical abuse, while 57% of those homozygous for the major allele reported anhedonia, only 29% of those who were carriers of the minor allele reported it (p < 0.02). rs1049353 also buffered the effects of childhood physical abuse on major depressive disorder, however this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, where minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse.
Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer and hence, future studies should carefully examine its impact on expression and conformational variation in CNR1, particularly in relation to stress adaptation.
PMCID: PMC3706194  PMID: 22393204
CNR1; endocannabinoid; physical abuse; rs1049353; GxE; anhedonia; major depression
8.  No association of candidate genes with cannabis use in a large sample of Australian twin families 
Addiction Biology  2011;17(3):687-690.
While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (N=7452) was used to test for association between ten previously reported candidate genes and lifetime frequency of cannabis use using a gene-based association test. None of the candidate genes reached even nominal significance (p<.05). The lack of replication may point to our limited understanding of the neurobiology of cannabis involvement and also to potential publication bias and false-positive findings in previous studies.
PMCID: PMC3393887  PMID: 21507154
genes; cannabis; genetics; association
9.  Parent, sibling and peer influences on smoking initiation, regular smoking and nicotine dependence. Results from a genetically informative design 
Addictive Behaviors  2011;37(3):240-247.
We sought to determine whether parenting, sibling and peer influences are associated with offspring ever smoking, regular smoking and nicotine dependence (ND) after controlling for familial factors. We used a twin-family design and data from structured diagnostic surveys of 1,919 biological offspring (age 12–32 years), 1,107 twin fathers, and 1,023 mothers. Offspring were classified into one of four familial risk groups based on twin fathers' and their co-twins' history of DSM-III-R nicotine dependence. Multivariate multinomial logistic regression was used to model familial risk, paternal and maternal parenting behavior and substance use, sibling substance use, and friend and school peer smoking, alcohol and drug use. Ever smoking was associated with increasing offspring age, white race, high maternal pressure to succeed in school, sibling drug use, and friend smoking, alcohol and drug use. Offspring regular smoking was associated with these same factors with additional contribution from maternal ND. Offspring ND was associated with increasing offspring age, male gender, biological parents divorce, high genetic risk from father and mother ND, maternal problem drinking, maternal rule inconsistency and sibling drug use, and friend smoking, alcohol and drug use. Friend smoking had the largest magnitude of association with offspring smoking. This effect remains after accounting for familial liability and numerous parent and sibling level effects. Smoking interventions may have greatest impact by targeting smoking prevention among peer groups in adolescent and young adult populations.
PMCID: PMC3374497  PMID: 22094168
smoking; nicotine dependence; peers; gene and environment
11.  Risk for Suicidal Thoughts and Behavior after Childhood Sexual Abuse in Women and Men 
Earlier studies have found an elevated risk for psychopathology and suicidal behavior associated with childhood sexual abuse (CSA); however the degree to which risk is mediated by depression and post-traumatic stress disorder (PTSD) in women and men remains unclear. We examined these issues in data from a family study of childhood maltreatment (N=2559). We found significant CSA-associated risk for depression, PTSD, and suicidal behavior for women and men. In survival analyses controlling for these disorders, we observed persistent, but somewhat reduced, CSA-associated risk for suicidal ideation and suicide attempt. Our findings thus suggest these disorders partially mediate CSA-associated risk.
PMCID: PMC3518050  PMID: 21599726
12.  Patterns of use, sequence of onsets and correlates of tobacco and cannabis 
Addictive behaviors  2011;36(12):1141-1147.
While most individuals initiate their use of tobacco prior to onset of cannabis use, recent reports have identified a smaller subset of youth who report onset of cannabis use prior to tobacco use. In this study, we characterize patterns of cannabis and tobacco use (tobacco but not cannabis, cannabis but not tobacco or both) and compare the factors associated with onset of tobacco before cannabis and cannabis before tobacco.
Data on 1812 offspring aged 12–32 years, drawn from two related offspring of Vietnam Era twin studies, were used. Individuals were divided into tobacco but not cannabis (T), cannabis but not tobacco (C) and users of both substances (CT). Those who used both could be further classified by the timing of onset of tobacco and cannabis use. Multinomial logistic regression was used to characterize the groups using socio-demographic and psychiatric covariates. Furthermore, data on parental smoking and drug use was used to identify whether certain groups represented greater genetic or environmental vulnerability.
22% (n=398) reported T, 3% (n=55) reported C and 44% reported CT (n=801). Of the 801 CT individuals, 72.8% (n=583), 9.9% (n=77) and 17.3% (n=139) reported onset of tobacco before cannabis, cannabis before tobacco and onsets at the same age. C users were as likely as CT users to report peer drug use and psychopathology, such as conduct problems while CT was associated with increased tobacco use relative to T. Onset of tobacco prior to cannabis, when compared onset of cannabis before tobacco or reporting initiation at the same age was associated with greater cigarettes smoked per day, however no distinct factors distinguished the group with onset of cannabis before tobacco from those with initiation at the same age.
A small subset of individuals report cannabis without tobacco use. Of those who use both cannabis and tobacco, a small group report cannabis use prior to tobacco use. Follow-up analyses that chart the trajectories of these individuals will be required to delineate their course of substance involvement.
PMCID: PMC3183489  PMID: 21820810
Cannabis; Tobacco; Reverse Gateways
13.  GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors 
Human Molecular Genetics  2011;20(22):4504-4514.
Serum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discover genetic variants affecting BCHE activity, and to clarify whether the associations between BCHE activity and cardiometabolic risk factors are caused by variation in BCHE or whether BCHE variation is secondary to the metabolic abnormalities. We measured serum BCHE in adolescents and adults from three cohorts of Australian twin and family studies. The genotypes from ∼2.4 million single-nucleotide polymorphisms (SNPs) were available in 8791 participants with BCHE measurements. We detected significant associations with BCHE activity at three independent groups of SNPs at the BCHE locus (P = 5.8 × 10−262, 7.8 × 10−47, 2.9 × 10−12) and at four other loci: RNPEP (P = 9.4 × 10−16), RAPH1-ABI2 (P = 4.1 × 10−18), UGT1A1 (P = 4.0 × 10−8) and an intergenic region on chromosome 8 (P = 1.4 × 10−8). These loci affecting BCHE activity were not associated with metabolic risk factors. On the other hand, SNPs in genes previously associated with metabolic risk had effects on BCHE activity more often than can be explained by chance. In particular, SNPs within FTO and GCKR were associated with BCHE activity, but their effects were partly mediated by body mass index and triglycerides, respectively. We conclude that variation in BCHE activity is due to multiple variants across the spectrum from uncommon/large effect to common/small effect, and partly results from (rather than causes) metabolic abnormalities.
PMCID: PMC3196893  PMID: 21862451
14.  Genome-wide association study identifies two loci strongly affecting transferrin glycosylation 
Human Molecular Genetics  2011;20(18):3710-3717.
Polysaccharide sidechains attached to proteins play important roles in cell–cell and receptor–ligand interactions. Variation in the carbohydrate component has been extensively studied for the iron transport protein transferrin, because serum levels of the transferrin isoforms asialotransferrin + disialotransferrin (carbohydrate-deficient transferrin, CDT) are used as biomarkers of excessive alcohol intake. We conducted a genome-wide association study to assess whether genetic factors affect CDT concentration in serum. CDT was measured in three population-based studies: one in Switzerland (CoLaus study, n = 5181) and two in Australia (n = 1509, n = 775). The first cohort was used as the discovery panel and the latter ones served as replication. Genome-wide single-nucleotide polymorphism (SNP) typing data were used to identify loci with significant associations with CDT as a percentage of total transferrin (CDT%). The top three SNPs in the discovery panel (rs2749097 near PGM1 on chromosome 1, and missense polymorphisms rs1049296, rs1799899 in TF on chromosome 3) were successfully replicated , yielding genome-wide significant combined association with CDT% (P = 1.9 × 10−9, 4 × 10−39, 5.5 × 10−43, respectively) and explain 5.8% of the variation in CDT%. These allelic effects are postulated to be caused by variation in availability of glucose-1-phosphate as a precursor of the glycan (PGM1), and variation in transferrin (TF) structure.
PMCID: PMC3159549  PMID: 21665994
15.  Reporting Bias in the Association Between Age at First Alcohol Use and Heavy Episodic Drinking 
Given the weight placed on retrospective reports of age at first drink in studies of later drinking-related outcomes, it is critical that its reliability be established and possible sources of systematic bias be identified. The overall aim of the current study is to explore the possibility that the estimated magnitude of association between early age at first drink and problem alcohol use may be inflated in studies using retrospectively reported age at alcohol use onset.
The sample was comprised of 1,716 participants in the Missouri Adolescent Female Twin Study who reported an age at first drink in at least 2 waves of data collection (an average of 4 years apart). Difference in reported age at first drink at Time 2 vs. Time 1 was categorized as 2 or more years younger, within 1 year (consistent), or 2 or more years older. The strength of the association between age at first drink and peak frequency of heavy episodic drinking (HED) at Time 1 was compared with that at Time 2. The association between reporting pattern and peak frequency of HED was also examined.
A strong association between age at first drink and HED was found for both reports, but it was significantly greater at Time 2. Just over one-third of participants had a 2 year or greater difference in reported ageat first drink. The majority of inconsistent reporters gave an older age at Time 2 and individuals with this pattern of reporting engaged in HED less frequently than consistent reporters.
The low rate of HED in individuals reporting an older age at first drink at Time 2 suggests that the upward shift in reported age at first drink among early initiates is most pronounced for light drinkers. Heavy drinkers may therefore be overrepresented among early onset users in retrospective studies, leading to inflated estimates of the association between early age at initiation and alcohol misuse.
PMCID: PMC3128178  PMID: 21438885
age at first drink; heavy episodic drinking; reporting bias
16.  Deconstructing the Architecture of Alcohol Abuse and Dependence Symptoms in a Community Sample of Late Adolescent and Emerging Adult Women: An Item Response Approach 
Drug and alcohol dependence  2011;116(1-3):222-227.
The objective of this study was to examine the underlying factorial architecture of lifetime DSM-IV alcohol use disorder (AUD) criteria in a population-based sample of adolescent and emerging adult female twins who had ever used alcohol (n=2832; aged 18-25 years), and to determine whether thresholds and factor loadings differed by age. Item response modeling was applied to DSM-IV AUD criteria. Compound criteria (e.g., persistent desire or unsuccessful attempts to quit or cut down) were included as separate items. Of the remaining 16 items, tolerance and use despite physical problems were the most and least commonly endorsed items, respectively. Underlying the items was a single factor representing liability to AUDs. Factor loadings ranged from 0.67 for blackouts to 0.90 for time spent using/recovering from effects. Some items assessing different DSM-IV criteria had very similar measurement characteristics, while others assessing the same criterion showed markedly different thresholds and factor loadings. Compared to that of women aged 21-25 years, the threshold for hazardous use was higher in women aged 18-20 years, but lower for used longer than intended and persistent desire to cut down. After accounting for threshold differences, no variations in discrimination across age groups were observed. In agreement with the extant literature, our findings indicate that the factorial structure of AUD is unidimensional, with no support for the abuse/dependence distinction. Individual components of compound criteria may differ in measurement properties; therefore pooling information from such divergent items will reduce information about the AUD construct.
PMCID: PMC3135415  PMID: 21306836
alcohol use disorder; item response modeling; twins
17.  A candidate gene association study of alcohol consumption in young women 
Excessive alcohol consumption contributes to significant morbidity and mortality. Heritable influences contribute to 50% of the variation in alcohol consumption, suggesting the important role of genes. We used data on a previously defined alcohol consumption factor score in a sample of 827 young women to investigate association with 1014 single nucleotide polymorphisms in genes related to addiction.
Data were drawn from the Missouri Adolescent Female Twin Study (MOAFTS) with replication in the College Drinking Sample (CDS). Genotypic and phenotypic data were available on 827 MOAFTS and 100 CDS women of European- American ancestry. Data on 1014 SNPs across 130 genes related to addiction were utilized. Association was conducted in QTDT, which allows for identity-by-descent information to account accurately for twin status in the analysis. The total association variance components model was used, with specification of variance components for relatedness in MOAFTS.
The top signals included clusters of SNPs in TPH2 (e.g. rs1386496, p=0.0003) and DDC (e.g. rs3779084, p=0.0008), genes that encode proteins responsible for serotonin synthesis. Additional polymorphisms in ADH1B, ADH1C, ADH7 and ADH1A1 were also associated at p < 0.05. The FDR for the top signal (p=0.0003) was 0.15 suggesting nominal significance only. Replication was limited and noted for 2 SNPs in ADH1C.
While no results survive the burden of multiple testing, nominal findings in TPH2 and DDC suggest the potential role of the serotonin synthesis pathway in alcohol consumption.
PMCID: PMC3239405  PMID: 21143251
18.  Age at Trauma Exposure and PTSD Risk in a Young Adult Female Sample 
Journal of traumatic stress  2010;23(6):811-814.
The aim of the current study was to test the independent and joint contributions of 8 different types of trauma to posttraumatic stress disorder (PTSD) risk using data from a young adult female cohort. Associations of traumatic events with PTSD onset were examined using Cox proportional hazards models. Differences in risk as a function of age at trauma were tested. Childhood sexual assault, physical abuse, and neglect were stronger predictors of PTSD onset than adolescent/early adult occurrence of these events in individual models. In a model including all traumatic events, differential risk by age remained for sexual assault and physical abuse. Early sexual assault was the strongest predictor of risk but additional traumatic events increased risk even in its presence.
PMCID: PMC3121097  PMID: 20963847
Addictive behaviors  2010;35(11):983-988.
Little is known about the relationship between relative body weight and transition from experimentation to regular smoking in young adult women. In the current study, data from 2494 participants in wave 4 of the Missouri Adolescent Female Twin Study (aged 18-29 years) who reported ever smoking a cigarette were analyzed using logistic regression. Body mass index (BMI) at time of interview was categorized according to CDC adult guidelines, and regular smoking was defined as having ever smoked 100 or more cigarettes and having smoked at least once a week for two months in a row. Since the OR’s for the overweight and obese groups did not differ significantly from one another in any model tested, these groups were combined. Forty-five percent of women who had ever smoked had become regular smokers. Testing of interactions between potential covariates and levels of the categorical BMI variable revealed a significant interaction between overweight/obesity and childhood sexual abuse (CSA; p<0.001) associated with regular smoking. Among women reporting CSA, the association between overweight/obesity and having become a regular smoker was negative (n=374; OR=0.48, 95% CI: 0.28-0.81). Both underweight and overweight/obesity were positively associated with transition to regular smoking among women who did not report CSA (n=2076; OR=1.57, 95% CI: 1.05-2.35 and OR=1.73, 95% CI: 1.35-2.20, respectively). These results suggest that experiencing CSA alters the association between BMI and regular smoking in women who have experimented with cigarettes.
PMCID: PMC3071024  PMID: 20634004
Smoking; body mass index; childhood sexual abuse; twins; MOAFTS
20.  A genome-wide association study of Cloninger’s Temperament scales: Implications for the evolutionary genetics of personality 
Biological psychology  2010;85(2):306-317.
Variation in personality traits is 30% to 60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger’s temperament scales in a sample of 5117 individuals, in order to identify common genetic variants underlying variation in personality. Participants’ scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for association with 1,252,387 genetic markers. We also performed gene-based association tests and biological pathway analyses. No genetic variants that significantly contribute to personality variation were identified, while our sample provides over 90% power to detect variants that explain only 1% of the trait variance. This indicates that individual common genetic variants of this size or greater do not contribute to personality trait variation, which has important implications regarding the genetic architecture of personality and the evolutionary mechanisms by which heritable variation is maintained.
PMCID: PMC2963646  PMID: 20691247
genome-wide association; genes; personality; temperament; mutation; selection; maintenance of genetic variation; evolution
21.  Peer substance involvement modifies genetic influences on regular substance involvement in young women 
Addiction (Abingdon, England)  2010;105(10):1844-1853.
Peer substance involvement (PSI) is a robust correlate of adolescent substance use. A small number of genetically informative studies suggest that shared genetic and environmental factors contribute to this association but have not clarified our understanding of the mechanisms by which PSI influences the etiology of regular substance involvement (RSI), particularly in women.
We use data on 2,176 twin women, who were part of a population-based cohort from U.S. Midwest, to examine the relationship between self-reported PSI during adolescence and a composite regular substance involvement factor (RSI) representing regular tobacco, alcohol and cannabis use during young adulthood, using genetically informative correlation, moderation and joint correlation-moderation models.
There was evidence for a significant additive genetic X environment interaction. PSI was moderately heritable (h2=0.25). Genetic, shared and non-shared influences on RSI overlapped with influences on PSI, with common genetic factors accounting for 18.5% of the genetic influences on RSI. Even after controlling for these shared genetic influences, RSI was more heritable in those reporting greater PSI.
While young women may select peers based on certain dispositional traits (e.g. permissiveness towards substance use), the social milieu constructed by PSI does modify the architecture of increased RSI in those individuals with increasing levels of PSI being associated with stronger expression of heritable influences.
PMCID: PMC3046802  PMID: 20569232
22.  Genetic epidemiology of self-reported lifetime DSM-IV major depressive disorder in a population-based twin sample of female adolescents 
In adults, about 40% of the variance in risk of Major Depressive Disorder (MDD) is due to genetic factors, but little data exist on the heritability of youth MDD. The goal of this study was the genetic analysis of MDD in an epidemiologically and genetically representative sample of adolescent female twins.
A sample of 3416 female adolescent twins systematically ascertained from birth records was assessed using a structured telephone interview that included a comprehensive DSM-IV-based section for the diagnostic assessment of MDD. Mean subject age at time of assessment was 15.5 and participation rate exceeded 85%. Genetic modeling was conducted taking into consideration the problem of censoring, i.e., that younger adolescents were not through their period of risk for adolescent onset of MDD.
Lifetime self-reported MDD prevalence ranged from 1% under age 12 to 17.4% at age 19 and older. The genetic variance in risk of MDD was 40.4% (95% confidence interval (CI): 23.9–55.1), with the remaining variance explained by non-shared environmental effects 59.6% (95%CI: 44.9–76.1). Shared environmental effects were not significant. A significant recall bias was observed with older respondents on average reporting later onsets for their first episode of MDD.
The genetic and environmental contributions to risk of MDD in this representative sample of female adolescent twins are remarkably analogous to findings from adult samples. These results are congruent with a conceptualization of adolescent MDD and adult MDD as having very similar etiologic determinants.
PMCID: PMC3152442  PMID: 14531581
Major Depressive Disorder; genetic epidemiology; adolescent twin studies
23.  Initial Response to Cigarettes Predicts Rate of Progression to Regular Smoking: Findings from an Offspring-of-Twins Design 
Addictive behaviors  2010;35(8):771-778.
The aim of this study was to examine the association between initial subjective effects from cigarettes and the rate of progression from first cigarette to regular smoking. Latent class analysis (LCA) was applied to subjective effects data from 573 offspring of twins ranging in age from 14 to 32 years. LCA revealed four classes: 1) High on both pleasurable and physiological respondeses, 2) Cough only response, 3) High on physiological, low on pleasurable respondses, and 4) High on pleasurable, low on physiological respondses. Classes of responses were then used to predict time from first cigarette to the onset of regular smoking in a Cox proportional hazards model. Time-varying covariates representing relevant psychiatric and psychosocial factors as well as dummy variables representing the offspring-of-twins design were included in the model. Members of classes 1 and 4 transitioned more rapidly to regular smoking than the classes characterized as low on the pleasurable response dimension. Our findings provide evidence that previously reported associations between pleasurable initial experiences and progression to regular smoking hold true as well for the rate at which that transition occurs. Furthermore, the fact that profiles of responses did not fall into global categories of exclusively pleasurable vs. exclusively negative (physiological) responses suggests the importance of considering both dimensions in combination to characterize risk for smoking-related outcomes.
PMCID: PMC2872050  PMID: 20385446
smoking; subjective effects; offspring of twins
24.  Common Genetic Contributions to Alcohol and Cannabis Use and Dependence Symptomatology 
Despite mounting evidence that use of and dependence on alcohol and cannabis are influenced by heritable factors, the extent to which heritable influences on these phenotypes overlap across the two substances has only rarely been explored. In the current study, we quantified cross-substance overlap in sources of variance and estimated the degree to which within-substance associations between use and dependence measures are attributable to common genetic and environmental factors for alcohol and cannabis.
The sample was comprised of 6,257 individuals (2,761 complete twin pairs and 736 singletons) from the Australian Twin Registry, aged 24-36 years. Alcohol and cannabis use histories were collected via telephone diagnostic interviews and used to derive an alcohol consumption factor, a frequency measure for cannabis use, and DSM-IV alcohol and cannabis dependence symptom counts. Standard genetic analyses were conducted to produce a quadrivariate model that provided estimates of overlap in genetic and environmental influences across the four phenotypes.
Over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms, and just under 50% of variance in alcohol dependence (AD) symptoms were attributable to genetic sources. Shared environmental factors did not contribute significantly to the four phenotypes. Nearly complete overlap in heritable influences was observed for within-substance measures of use and dependence symptoms. Genetic correlations across substances were 0.68 and 0.62 for use and dependence symptoms, respectively.
Common heritable influences were evident for alcohol and cannabis use and for AD and cannabis dependence symptomatology, but findings indicate that substance-specific influences account for the majority of the genetic variance in the cannabis use and dependence phenotypes. By contrast, the substantial correlations between alcohol use and AD symptoms and between cannabis use and cannabis dependence symptoms suggest that measures of heaviness of use capture much of the same genetic liability for alcohol- and cannabis-related problems as dependence symptomatology.
PMCID: PMC3089946  PMID: 20028363
alcohol dependence; cannabis dependence; genetics; twins
25.  Alcohol Consumption Indices of Genetic Risk for Alcohol Dependence 
Biological psychiatry  2009;66(8):795-800.
Previous research has reported a significant genetic correlation between heaviness of alcohol consumption and alcohol dependence (AD), but this association might be driven by the influence of AD on consumption rather than the reverse. We test the genetic overlap between AD symptoms and a heaviness of consumption measure among individuals who do not have AD. A high genetic correlation between these measures would suggest that a continuous measure of consumption may have a useful role in the discovery of genes contributing to dependence risk.
Factor analysis of 5 alcohol use measures was used to create a measure of heaviness of alcohol consumption. Quantitative genetic analyses of interview data from the 1989 Australian Twin Panel (n=6257 individuals; M=29.9 years) assessed the genetic overlap between heaviness of consumption, DSM-IV AD symptoms, DSM-IV AD symptom clustering, and DSM-IV alcohol abuse.
Genetic influences accounted for 30–51% of the variance in the alcohol measures and genetic correlations were 0.90 or higher for all measures, with the correlation between consumption and dependence symptoms among non-dependent individuals estimated at 0.97 (95% CI: 0.80–1.00).
Heaviness of consumption and AD symptoms have a high degree of genetic overlap even among non-dependent individuals in the general population, implying that genetic influences on dependence risk in the general population are acting to a considerable degree through heaviness of use, and that quantitative measures of consumption will likely have a useful role in the identification of genes contributing to AD.
PMCID: PMC3077105  PMID: 19576574
alcohol dependence; heaviness of consumption; heritability; genetic overlap; twins; gene identification

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