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1.  A Genome-Wide Association Study of Sleep Habits and Insomnia 
Several aspects of sleep behaviour such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of 6 sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317K, 370K and 610K arrays and the common Single Nucleotide Polymorphisms between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the 3rd intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (p = 1.3 × 10−6). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (p = 0.73). We have identified several other associations that await replication in an independent sample. Our study had good power to detect common single nucleotide polymorphisms that explain more than 2% of the phenotypic variance in self-report sleep phenotypes at a genome-wide significant level. No such variants were detected.
PMCID: PMC4083458  PMID: 23728906
insomnia; genetics; mood; sleep; circadian
2.  DSM-IV defined conduct disorder and oppositional defiant disorder: An investigation of shared liability in female twins 
Psychological medicine  2014;44(5):1053-1064.
DSM-IV specifies a hierarchal diagnostic structure such that an ODD diagnosis is applied only if criteria are not met for CD. Genetic studies of ODD and CD support a combination of shared genetic and environmental influences, but largely ignore the imposed diagnostic structure.
We examined whether ODD and CD share an underlying etiology while accounting for DSM-IV diagnostic specifications. Data from 1446 female twin pairs, aged 11–19, were fitted to two-stage models adhering to the DSM-IV diagnostic hierarchy.
Models suggested that DSM-IV ODD-CD covariation is attributed largely to shared genetic influences.
This is the first study, to our knowledge, to examine genetic and environmental overlap among these disorders while maintaining DSM-IV hierarchical structure. Findings reflect primarily shared genetic influences and specific (i.e., uncorrelated) shared/familial environmental effects on these DSM-IV defined behaviors. These results have implications for how best to define CD and ODD for future genetically-informed analyses.
PMCID: PMC4024101  PMID: 23795654
adolescence; conduct disorder; genetics; oppositional defiant disorder; twins
3.  Effects of Sibship Size and Composition on Younger Brothers’ and Sisters’ Alcohol Use Initiation: Findings from an Australian Twin Sample 
The effects of sibship size and structure on delinquency are well established. Specifically, having a large family and many brothers has been shown to predict offending. However, despite strong links between delinquency and alcohol use, the contribution of sibship factors to drinking behaviors remains largely unexplored. The current study investigated the impact of sibship size and composition on younger brothers’ and sisters’ ages of drinking and intoxication onset.
We employed a sample of 4,281 same-sex twins from the Australian Twin Register to examine whether: (1) large sibship size facilitates earlier age at first drink (AFD) and age at first intoxication (AFI) in males and females; (2) having many older brothers predicts earlier ages of AFD and AFI in males; and (3) having many older brothers results in later AFD and AFI in females. We tested whether effects were moderated by parental divorce and alcohol misuse and mediated by familial religion.
Sibling effects were minimal before accounting for family context. However, when parental divorce and excessive parental drinking were included as moderators, sibling effects were significantly amplified among individuals from homes of divorce, and effects were strongest when siblings were close in age.
Strong close in age older (CIAO) sibling effects indicate that proximal sibling attitudes and behaviors about alcohol likely interact with structural factors to influence younger siblings' drinking. Sibship factors were much more influential in one population (individuals from homes of divorce) than another (respondents with parental history of excessive drinking), suggesting that sibling effects vary depending on the type of co-occurring familial risk. Prevention efforts performed at the family level, and introduced before first use of alcohol, are likely to delay drinking initiation and help prevent future alcohol problems.
PMCID: PMC3631572  PMID: 23278275
age at first drink; siblings; sibship composition; close in age; twins
4.  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
5.  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
6.  Metabolic and biochemical effects of low-to-moderate alcohol consumption 
Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of two to four drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analysed the dose-response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to three drinks per day.
Biochemical tests were performed on serum from 8396 study participants (3750 men and 4646 women, aged 51 ± 13 years, range 18–93) who had provided information on alcohol consumption in the week preceding blood collection.
GGT, ALT, AST, CDT, urate, ferritin and bilirubin showed little or no change with alcohol consumption below two to three drinks per day, but increased with higher intake. HDL-C and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting one to two drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase and butyrylcholinesterase. Increasing alcohol use was associated with decreasing LDL-C in younger women, but higher LDL-C in older men.
Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality.
PMCID: PMC3568441  PMID: 23134229
Alcohol; Biomarkers; Dose-response curve; Population study
7.  ANKK1, TTC12, and NCAM1 Polymorphisms and Heroin Dependence – importance of considering drug exposure 
JAMA psychiatry (Chicago, Ill.)  2013;70(3):325-333.
The genetic contribution to liability for opioid dependence is well-established; identification of the responsible genes has proved challenging.
To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.
Case-control genetic association study that included two control groups (lacking an established optimal control group).
Semi-structured psychiatric interviews
Australian cases (N=1459) ascertained from opioid replacement therapy (ORT) clinics, neighborhood controls (N=531) ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and unrelated Australian Twin Registry (ATR) controls (N=1495) not dependent on alcohol or illicit drugs selected from a twin and family sample.
Main Outcome Measure
Lifetime heroin dependence
Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (p≥.01); a similar comparison to neighborhood controls revealed greater differences (p≥1.8 × 10−4). Comparing cases (N=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (N=340), three SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 [most strongly associated; odds ratio 1.59; 95%CI (1.32–1.92); p=9.7 × 10−7], ANKK1 SNP rs4938013 and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (N=191) and non-dependent (N=340) neighborhood controls, suggesting that liability likely extends to non-opioid illicit drug dependence. Aggregate heroin dependence risk associated with two SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (p= 2.74 × 10−9 for the risk-associated linear trend).
Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.
PMCID: PMC3789525  PMID: 23303482
8.  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
9.  The long-term stability of the human gut microbiota 
Science (New York, N.Y.)  2013;341(6141):1237439.
A low-error 16S rRNA amplicon sequencing method (LEA-Seq) plus whole genome sequencing of >500 cultured isolates were used to characterize bacterial strain composition in the fecal microbiota of 37 USA adults sampled for up to five years. Microbiota stability follows a power law function which, when extrapolated, suggests that most strains in an individual are residents for decades. Shared strains were recovered from family members, but not from unrelated individuals. Sampling individuals for up to 32 weeks while consuming a monotonous liquid diet indicated that changes in weight are more predictive of changes in strain composition than sampling interval. This combination of stability and responsiveness to physiologic change confirms the potential of the gut microbiota as a diagnostic tool and therapeutic target.
PMCID: PMC3791589  PMID: 23828941
10.  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
11.  Modeling the direction of causation between cross-sectional measures of disrupted sleep, anxiety and depression in a sample of male and female Australian twins 
Journal of sleep research  2012;21(6):675-683.
The direction of causation between measures of disrupted sleep, anxiety and depression is not well understood. Under certain conditions, cross sectional analysis based on genetically informative data can provide important information about the direction of causation between variables. Two community-based samples of 7,235 Australian twins aged 18 to 87 years were mailed an extensive questionnaire that covered a wide range of personality and behavioral measures. Included were self-report measures of disrupted sleep as well as symptoms of anxiety and depression. Among all females, modeling the direction of causation did not support the hypothesis of sleep having a direct causal impact on risk of anxiety or depression. Among older females, we found evidence that both anxiety and depression interact reciprocally with disrupted sleep whereas among younger women, both anxiety and depression appear to have a causal impact on sleep. Results for males were equivocal. The nosological implications of our findings are discussed.
PMCID: PMC3461239  PMID: 22738694
Disrupted sleep; anxiety; depression; twins; genes; environment; direction of causation
12.  Association between in vivo alcohol metabolism and genetic variation in pathways that metabolize the carbon skeleton of ethanol and NADH reoxidation in the Alcohol Challenge Twin Study 
Variation in alcohol metabolism affects the duration of intoxication and alcohol use. While the majority of genetic association studies investigating variation in alcohol metabolism have focused on polymorphisms in alcohol or aldehyde dehydrogenases, we have now tested for association with genes in alternative metabolic pathways that catalyze the carbon skeleton of ethanol and NADH reoxidation.
950 single nucleotide polymorphisms (SNPs) spanning 14 genes (ACN9, ACSS1, ACSS2, ALDH1A1, CAT, CYP2E1, GOT1, GOT2, MDH1, MDH2, SLC25A10, SLC25A11, SLC25A12, SLC25A13) were genotyped in 352 young adults who participated in an alcohol challenge study. Traits tested were blood and breath alcohol concentration, peak alcohol concentration and rates of alcohol absorption and elimination. Allelic association was tested using quantitative univariate and multivariate methods.
A CYP2E1 promoter SNP (rs4838767, minor allele frequency 0.008) exceeded the threshold for study-wide significance (4.01 × 10−5) for two early blood alcohol concentration (BAC), eight breath alcohol concentration (BrAC) measures and the peak BrAC. For each phenotype the minor C-allele was related to a lower alcohol concentration, most strongly for the fourth BrAC (P = 2.07 × 10−7) explaining ~8% of the phenotypic variance. We also observed suggestive patterns of association with variants in ALDH1A1 and on chromosome 17 near SLC25A11 for aspects of blood and breath alcohol metabolism. A SNP upstream of GOT1 (rs2490286) reached study-wide significance for multivariate BAC metabolism (P = 0.000040).
Overall, we did not find strong evidence that variation in genes coding for proteins that further metabolize the carbon backbone of acetaldehyde, or contribute to mechanisms for regenerating NAD from NADH, affects alcohol metabolism in our European-descent subjects. However, based on the breath alcohol data, variation in the promoter of CYP2E1 may play a role in pre-absorptive or early hepatic alcohol metabolism, but more samples are required to validate this finding.
PMCID: PMC3729587  PMID: 22577853
alcohol metabolism; association; genetics; CYP2E1; alcohol challenge
13.  Substantial Genetic Overlap between Schizotypy and Neuroticism: A Twin Study 
Behavior genetics  2012;42(5):10.1007/s10519-012-9558-6.
Schizotypy is phenotypically associated with neuroticism. To reveal the origin of this association, we assessed 3349 (1449 monozygotic (MZ), 1105 dizygotic (DZ) same-sex and 795 DZ opposite-sex) twins on a 12-item version of Chapman’s Psychosis-Proneness Scales and the short-form of the Eysenck Personality Questionnaire-Revised as measures of schizotypy and neuroticism.
A substantial proportion (.51 with 95% CI from .38 to .64) of the phenotypic correlation of .37 between neuroticism and the perceptual and ideational components of schizotypy was accounted for by shared genetic influences on these two traits. Moreover, a Cholesky decomposition including anhedonia, hypomania and impulsivity fully accounted for the heritable variance in perceptual and ideational components of schizotypy.
These findings suggest a shared genetic etiology between neuroticism and perceptual and ideational components of schizotypy and affect future investigations on the etiology of these phenotypically overlapping traits and affective and psychotic disorders.
PMCID: PMC3816282  PMID: 22955548
Perceptual aberration; Magical ideation; Phenotypic correlation; Behavior genetics; Schizotypy; Neuroticism
14.  Genetic and Environmental Transmission of Body Mass Index Fluctuation 
Behavior genetics  2012;42(6):867-874.
This study sought to determine the relationship between BMI fluctuation and cardiovascular disease phenotypes, diabetes, and depression and the role of genetic and environmental factors in individual differences in BMI fluctuation using the extended twin-family model (ETFM).
Study Design and Methods
This study included 14,763 twins and their relatives. Health and Lifestyle Questionnaires were obtained from 28,492 individuals from the Virginia 30,000 dataset including twins, parents, siblings, spouses, and children of twins. Self-report cardiovascular disease, diabetes, and depression data were available. From self-reported height and weight, BMI fluctuation was calculated as the difference between highest and lowest BMI after age 18, for individuals 18–80 years. Logistic regression analyses were used to determine the relationship between BMI fluctuation and disease status. The ETFM was used to estimate the significance and contribution of genetic and environmental factors, cultural transmission, and assortative mating components to BMI fluctuation, while controlling for age. We tested sex differences in additive and dominant genetic effects, parental, non-parental, twin, and unique environmental effects.
BMI fluctuation was highly associated with disease status, independent of BMI. Genetic effects accounted for ~34% of variance in BMI fluctuation in males and ~43% of variance in females. The majority of the variance was accounted for by environmental factors, about a third of which were shared among twins. Assortative mating, and cultural transmission accounted for only a small proportion of variance in this phenotype.
Since there are substantial health risks associated with BMI fluctuation and environmental components of BMI fluctuation account for over 60% of variance in males and over 50% of variance in females, environmental risk factors may be appropriate targets to reduce BMI fluctuation.
PMCID: PMC3474545  PMID: 23011216
BMI; Chronic Disease; Weight change; Heritability; Family Studies
15.  Responses to Alcohol and Cigarette Use During Ecologically Assessed Drinking Episodes 
Psychopharmacology  2012;223(3):331-344.
Tobacco and alcohol are frequently used together, and this may be partly explained by a distinct profile of subjective effects associated with co-administration. Ecological Momentary Assessment studies have examined effects of naturally occurring co-use, but, to date, have not assessed differing effects as alcohol levels rise and fall.
To describe subjective states and appraisals of cigarette and alcohol effects reported during the entirety of real-world drinking episodes.
Currently-smoking frequent drinkers (N = 255) carried electronic diaries for 21 days. Analyses focused on reports made during 2,046 drinking episodes. Signaled prompts intensively oversampled moments in the hours following consumption of the first drink in an episode. Multilevel regression analyses were used to predict ratings of buzz, dizziness, excitement, and sluggishness as a function of person-level and contextual covariates, estimated blood alcohol concentration (eBAC) level, ascending vs. descending eBAC, smoking, and their interactions. Appraisals of cigarette and alcohol effects were also examined within this framework.
Buzz, excitement, and pleasure from alcohol and cigarettes were prominent features of real-world drinking episodes. Smoking was associated with enhanced buzz and excitement when eBAC was high and descending. Smoking slightly accentuated the relation between eBAC and ratings of drinking pleasure among women, but this relation was somewhat weakened by smoking among men.
Smoking during drinking episodes may be partly be explained by a persistence of stimulant alcohol effects beyond the BAC peak. Acute effects of nicotine and tobacco use on the descending limb deserve further scrutiny in experimental alcohol challenge research.
PMCID: PMC3427832  PMID: 22538731
smoking; tobacco; alcohol; craving; reinforcement; subjective states; Ecological Momentary Assessment
16.  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
17.  Associations of Alcohol, Nicotine, Cannabis and Drug Use/Dependence with Educational Attainment: Evidence from Cotwin-Control Analyses 
Although substance use is associated with reduced educational attainment, this association may be due to common risk factors such as socioeconomic disadvantage. We tested whether alcohol, nicotine, and illicit drug use and dependence were associated with lifetime educational attainment after controlling for familial background characteristics.
Data were from a 1987 questionnaire and a 1992 telephone diagnostic interview of 6242 male twins (n=3121 pairs; mean age= 41.9 years in 1992) who served in the U.S. military during the Vietnam-era, and therefore were eligible for educational benefits after military service. Reduced educational attainment (less than 16 years) was examined in twin pairs discordant for substance use history. Substance use and dependence risk factors assessed were early alcohol and cannabis use, daily nicotine use, lifetime cannabis use, and alcohol, nicotine, cannabis, and any illicit drug dependence.
Three significant differences were observed between at risk twins and their cotwins: Compared to their low-risk cotwins, likelihood of completing less than 16 years of education was significantly increased for: (a) twins who used alcohol before age 18 (adjusted OR=1.44; 95%CI:1.02–2.05), (b) twins with a lifetime alcohol dependence diagnosis (adjusted OR=1.76; 95%CI: 1.27–2.44), and (c) twins who had used nicotine daily for 30 or more days (adjusted OR=2.54, 95%CI: 1.55–4.17). However, no differences in education were observed among twin pairs discordant for cannabis initiation, early cannabis use, or cannabis, nicotine, or any illicit drug dependence.
Even in a veteran population with access to military educational benefits, early alcohol use, alcohol dependence, and daily nicotine use remained significantly associated with years of education after controlling for shared familial contributions to educational attainment. The association between other substances and educational attainment was explained by familial factors common to these substance use phenotypes and adult educational attainment.
PMCID: PMC3412907  PMID: 22587016
cotwin-control design; early substance use; drug dependence; alcohol dependence; educational attainment
18.  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
19.  Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study 
The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers.
PMCID: PMC3709115  PMID: 23875064
Nicotinic acetylcholine receptors; 15q25.1; alcohol use; smoking behavior; public health; population-based sample; genetic association
20.  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
21.  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
22.  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
23.  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
24.  Genetic and Environmental Influences on the Rate of Progression to Alcohol Dependence in Young Women 
The development of alcohol dependence (AD) involves transitions through multiple stages of drinking behaviors and is shaped by both heritable and environmental influences. We attempted to capture this dynamic process by characterizing genetic and environmental contributions to the rate at which women progressed through 3 significant transitions along the pathway to AD: nonuse to initiation, initiation to onset of first alcohol-related problem, and first problem to onset of AD.
The sample consisted of 3,546 female twins from the Missouri Adolescent Female Twin Study. Participants ranged in age from 18 to 29 years. Retrospective reports of alcohol use histories were collected by telephone diagnostic interview and transition times between drinking milestones were coded ordinally. Standard genetic analyses were conducted in Mx to derive a trivariate model that provided estimates of genetic and environmental influences that were common as well as specific to the 3 transition times.
Heritable influences were found for rate of progression across all 3 transitions, accounting for 30 to 47% of the variance in transition times. Shared environmental contributions were evident only in rate of progression from nonuse to initiation (i.e., age at first drink). Heritable contributions to the rate of movement through successive drinking milestones were attributable to a common factor, whereas environmental influences were transition-specific.
The current study is unique in its use of a genetically informative design to document the rate of movement between drinking milestones in a female sample and to examine genetic contributions to multiple transition times over the course of AD development. Results indicate that an earlier report of heritability for males in rate of progression from regular drinking to AD generalizes to women and to other alcohol stage transitions. Findings also suggest the need to consider stage-specific environmental contributions to alcohol outcomes in developing interventions.
PMCID: PMC3593341  PMID: 18331380
Alcohol Dependence; Genetics; Women; Transition; Course

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