Dixie J. Statham

Accurate, Large-Scale Genotyping of 5HTTLPR and Flanking Single Nucleotide Polymorphisms in an Association Study of Depression, Anxiety, and Personality Measures

BACKGROUND The length polymorphism repeat in the promoter region of the serotonin transporter gene (5HTTLPR) is one of the most studied polymorphisms for association with a range of psychiatric and personality phenotypes. However, the original 5HTTLPR assay is prone to bias toward short allele calling. METHODS We designed new assays for the 5HTTLPR suitable for large-scale genotyping projects and we genotyped 13 single nucleotide polymorphisms (SNPs) in a 38-kilobase region around the 5HTTLPR, including SNP rs25531, a polymorphism of the 5HTTLPR long allele. Association analysis was conducted for major depression and/or anxiety disorder in unrelated cases (n = 1161) and control subjects (n = 1051) identified through psychiatric interviews administered to a large population sample of Australian twin families. Participants had been scored for personality traits several years earlier (n > or = 2643 unrelated individuals). RESULTS We identified a two-SNP haplotype proxy for 5HTTLPR; the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5HTTLPR (r(2) = .72). We found evidence for association (p = .0062, after accounting for multiple testing) for SLC6A4 SNPs rs6354 and rs2020936 (positioned in a different linkage disequilibrium [LD] block about 15.5 kb from 5HTTLPR) with anxiety and/or depression and neuroticism, with the strongest association for recurrent depression with onset in young adulthood (odds ratio = 1.55, 95% confidence interval = 1.16-2.06). CONCLUSIONS The associated SNPs are in the same LD block as the variable number of tandem repeats serotonin transporter intron 2 marker, for which association has previously been reported.

Common Heritable Contributions to Low-Risk Trauma, High-Risk Trauma, Posttraumatic Stress Disorder, and Major Depression

CONTEXT Understanding the relative contributions of genetic and environmental factors to trauma exposure, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) is critical to developing etiologic models of these conditions and their co-occurrence. OBJECTIVES 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. DESIGN 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. SETTING Structured psychiatric telephone interviews. PARTICIPANTS 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. RESULTS 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. CONCLUSIONS 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.

Measurement of alcohol craving.

Despite considerable research activity and application in treatment, the construct of craving remains poorly understood. We propose that cravings and urges are cognitive-emotional events in time, characterised by frequency, duration, intensity and salience. Commonly used measures of alcohol craving are reviewed, and their strengths and weaknesses identified. Most measures confound craving with behaviours, or with separable cognitive phenomena such as expectancies, intentions, or perceived behavioural control. These confounds have limited our advances in understanding the determinants and consequences of craving. Based on the criteria applied in this review, among the better performing multi-item measures are the Penn Alcohol Craving Scale and Obsessive subscale of the Obsessive-Compulsive Drinking Scale. Optimal assessment strategies are likely to involve daily assessments of peak intensity of cravings, desires or urges and of the frequency and duration of craving episodes. Of particular interest are measures of intensity at times when individuals are at risk of drinking or of other functional impacts from craving.

The Craving Experience Questionnaire: a brief, theory-based measure of consummatory desire and craving

BACKGROUND AND AIMS Research into craving is hampered by lack of theoretical specification and a plethora of substance-specific measures. This study aimed to develop a generic measure of craving based on elaborated intrusion (EI) theory. Confirmatory factor analysis (CFA) examined whether a generic measure replicated the three-factor structure of the Alcohol Craving Experience (ACE) scale over different consummatory targets and time-frames. DESIGN Twelve studies were pooled for CFA. Targets included alcohol, cigarettes, chocolate and food. Focal periods varied from the present moment to the previous week. Separate analyses were conducted for strength and frequency forms. SETTING Nine studies included university students, with single studies drawn from an internet survey, a community sample of smokers and alcohol-dependent out-patients. PARTICIPANTS A heterogeneous sample of 1230 participants. MEASUREMENTS Adaptations of the ACE questionnaire. FINDINGS Both craving strength [comparative fit indices (CFI = 0.974; root mean square error of approximation (RMSEA) = 0.039, 95% confidence interval (CI) = 0.035-0.044] and frequency (CFI = 0.971, RMSEA = 0.049, 95% CI = 0.044-0.055) gave an acceptable three-factor solution across desired targets that mapped onto the structure of the original ACE (intensity, imagery, intrusiveness), after removing an item, re-allocating another and taking intercorrelated error terms into account. Similar structures were obtained across time-frames and targets. Preliminary validity data on the resulting 10-item Craving Experience Questionnaire (CEQ) for cigarettes and alcohol were strong. CONCLUSIONS The Craving Experience Questionnaire (CEQ) is a brief, conceptually grounded and psychometrically sound measure of desires. It demonstrates a consistent factor structure across a range of consummatory targets in both laboratory and clinical contexts.

An Autosomal Linkage Scan for Cannabis Use Disorders in the Nicotine Addiction Genetics Project

CONTEXT Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors. OBJECTIVE To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders. DESIGN In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria. RESULTS A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the gamma-aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4). CONCLUSIONS Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.

Measuring alcohol craving: development of the Alcohol Craving Experience questionnaire

AIMS To develop a measure of craving based on the Elaborated Intrusion (EI) theory of desire and to examine the construct, concurrent and discriminant validity of the instrument. DESIGN Cross-sectional. SETTING AND PARTICIPANTS Patients from a hospital alcohol and drug out-patient service (n = 230), participants in a randomized controlled trial (n = 219) and students in a university-based study of alcohol craving (n = 202) were recruited. MEASUREMENTS The Alcohol Craving Experience questionnaire (ACE) was developed to measure sensory aspects of craving (imagining taste, smell or sensations of drinking and intrusive cognitions associated with craving) when craving was maximal during the previous week (ACE-S: strength), and to assess frequency of desire-related thoughts in the past week (ACE-F: frequency). All participants completed the ACE and the Alcohol Use Disorders Identification Test (AUDIT). The Obsessive Compulsive Drinking Scale (OCDS) and the Depression Anxiety and Stress Scale (DASS) were completed by hospital patients and randomized control trial participants. FINDINGS Exploratory factor analysis on the ACE-S and ACE-F resulted in a three-factor structure representing imagery, intensity and intrusion. An attempt to confirm this factor structure required a reduction in items (two from ACE-S, five from ACE-F) before a good fit to the three-factor model was obtained. Concurrent validity with the OCDS, with severity of alcohol dependence and with depression, anxiety and stress, was demonstrated. The ACE discriminated between clinical and non-clinical populations and between those at higher risk of alcohol dependence and those at lower risk. CONCLUSIONS A new scale, the Alcohol Craving Experience questionnaire, based on the Elaborated Intrusion theory of desire appears to capture key constructs of the theory and correlate with indices of alcohol dependence.

Measuring alcohol craving: development of the Alcohol Craving Experience questionnaire.

AIMS To develop a measure of craving based on the Elaborated Intrusion (EI) theory of desire and to examine the construct, concurrent and discriminant validity of the instrument. DESIGN Cross-sectional. SETTING AND PARTICIPANTS Patients from a hospital alcohol and drug out-patient service (n = 230), participants in a randomized controlled trial (n = 219) and students in a university-based study of alcohol craving (n = 202) were recruited. MEASUREMENTS The Alcohol Craving Experience questionnaire (ACE) was developed to measure sensory aspects of craving (imagining taste, smell or sensations of drinking and intrusive cognitions associated with craving) when craving was maximal during the previous week (ACE-S: strength), and to assess frequency of desire-related thoughts in the past week (ACE-F: frequency). All participants completed the ACE and the Alcohol Use Disorders Identification Test (AUDIT). The Obsessive Compulsive Drinking Scale (OCDS) and the Depression Anxiety and Stress Scale (DASS) were completed by hospital patients and randomized control trial participants. FINDINGS Exploratory factor analysis on the ACE-S and ACE-F resulted in a three-factor structure representing imagery, intensity and intrusion. An attempt to confirm this factor structure required a reduction in items (two from ACE-S, five from ACE-F) before a good fit to the three-factor model was obtained. Concurrent validity with the OCDS, with severity of alcohol dependence and with depression, anxiety and stress, was demonstrated. The ACE discriminated between clinical and non-clinical populations and between those at higher risk of alcohol dependence and those at lower risk. CONCLUSIONS A new scale, the Alcohol Craving Experience questionnaire, based on the Elaborated Intrusion theory of desire appears to capture key constructs of the theory and correlate with indices of alcohol dependence.

Overlapping Genetic and Environmental Influences on Nonsuicidal Self-injury and Suicidal Ideation: Different Outcomes, Same Etiology?

IMPORTANCE Nonsuicidal self-injury (NSSI) and suicidal self-injury are very harmful behaviors and are associated with several psychiatric disorders. In the recently developed fifth edition of the DSM, NSSI and suicidal behavior disorder are for the first time introduced as conditions in their own right instead of symptoms of other psychiatric disorders. It is unclear to what extent NSSI and suicidal self-injury share the same underlying biological mechanisms and are influenced by the same environmental factors. OBJECTIVE To determine the relative importance of genetic and environmental influences on the variation in NSSI and suicidal ideation and their covariation. DESIGN, SETTING, AND PARTICIPANTS Classical twin design using a sample of 10,678 male and female adult twins (mean [SD] age, 32.76 [6.99] years) from the Australian Twin Registry, a population-based twin registry. Between 1996 and 2009, the twins participated in semistructured telephone interviews that primarily focused on psychiatric disorders. MAIN OUTCOMES AND MEASURES Lifetime presence of self-reported NSSI and suicidal ideation. RESULTS The prevalences of NSSI and suicidal ideation were 4.7% and 26.5%, respectively, and individuals who engaged in self-harm were much more likely to report suicidal ideation (odds ratio = 8.39; 95% CI, 6.84-10.29). Results from a bivariate genetic model indicated that genetic factors explain a substantial part of the variance in both NSSI (37% for men and 59% for women) and suicidal ideation (41% for men and 55% for women), while residual influences (including nonshared environmental influences and measurement error) explain the remainder of the variance. Shared (family) environment did not seem to play a role. Moreover, both behaviors were strongly correlated (r = 0.49 for men and 0.61 for women), and this correlation was largely explained by overlapping genetic influences (76% for men and 62% for women), whereas residual influences accounted for the remainder of the phenotypic correlation. CONCLUSIONS AND RELEVANCE Results indicated that the substantial correlation between NSSI and suicidal ideation is largely driven by overlapping genetic factors, suggesting that the 2 behaviors share similar biological underpinnings. Overlapping residual influences also explain part of the covariance between the 2 traits. Future research should further investigate which genetic and environmental influences underlie the vulnerability to NSSI and suicidal ideation.

Common genetic contributions to alcohol and cannabis use and dependence symptomatology.

BACKGROUND 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 2 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. METHODS The sample was comprised of 6,257 individuals (2,761 complete twin pairs and 735 singletons) from the Australian Twin Registry, aged 24 to 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 4 phenotypes. RESULTS 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 4 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. CONCLUSIONS 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 to alcohol- and cannabis-related problems as dependence symptomatology.

Parental separation and early substance involvement: results from children of alcoholic and cannabis dependent twins

BACKGROUND Risks associated with parental separation have received limited attention in research on children of parents with substance use disorders. We examined early substance involvement as a function of parental separation during childhood and parental alcohol and cannabis dependence. METHOD Data were drawn from 1318 adolescent offspring of monozygotic (MZ) or dizygotic (DZ) Australian twin parents. Cox proportional hazards regression analyses were conducted predicting age at first use of alcohol, first alcohol intoxication, first use and first regular use of cigarettes, and first use of cannabis, from parental separation and both parent and cotwin substance dependence. Parent and cotwin alcohol and cannabis dependence were initially modeled separately, with post hoc tests for equality of effects. RESULTS With few exceptions, risks associated with parental alcohol versus cannabis dependence could be equated, with results largely suggestive of genetic transmission of risk from parental substance (alcohol or cannabis) dependence broadly defined. Controlling for parental substance dependence, parental separation was a strong predictor for all substance use variables, especially through age 13. CONCLUSION Together, findings underscore the importance of parental separation as a risk-factor for early substance involvement over and above both genetic and environmental influences specific to parental alcohol and cannabis dependence.