C/EBP delta and C/EBP gamma bind the CCAAT-box in the human beta-globin promoter and modulate the activity of the CACC-box binding protein, EKLF

Developmental- and tissue-specific expression of globin genes is mediated by a few key elements within the proximal promoter of each gene. DNA-binding assays previously identified NF-Y, GATA-1, C/EBP beta and C/EBP gamma as candidate regulators of beta-globin transcription via the CCAAT-box, a promoter element situated between CACC- and TATA-boxes. We have identified C/EBP delta as an additional beta-globin CCAAT-box binding protein. In reporter assays, we show that C/EBP delta can co-operate with EKLF, a CACC-box binding protein, to activate the beta-globin promoter, whereas C/EBP gamma inhibits the transcriptional activity of EKLF in this assay. (c) 2005 Elsevier B.V. All rights reserved.

The genetics of alcohol intake and of alcohol dependence

Background: Because alcohol has multiple dose-dependent consequences, it is important to understand the causes of individual variation in the amount of alcohol used. The aims of this study were to assess the long-term repeatability and genetic or environmental causes of variation in alcohol intake and to estimate the degree of overlap with causes of susceptibility to alcohol dependence. Methods: Data were used from three studies conducted between 1980 and 1995 on volunteer adult male and female Australian twin subjects. In each study, alcohol intake was reported both as quantity X frequency and as past-week data. Repeatability was calculated as correlations between occasions and between measures, and the effects of genes and environment were estimated by multivariate model fitting to the twin pair repeated measures of alcohol use. Relationships between mean alcohol use and the lifetime history of DSM-III-R alcohol dependence were tested by bivariate model fitting. Results: Repeatability of the alcohol intake measures was between 0.54 and 0.85, with the highest repeatability between measures within study and the lowest repeatability between the first and last studies. Reported alcohol consumption was mainly affected by genetic factors affecting all times of study and by nonshared environmental factors (including measurement error) unique to each time of study. Genes that affect alcohol intake do affect alcohol dependence, but genetic effects unique to dependence are also significant; environmental effects are largely unique to either intake and dependence. Conclusions: Nearly all the repeatable component of variation in alcohol intake is due to genetic effects. Genes affecting intake also affect dependence risk, but there are other genes that affect dependence alone. Studies aiming to identify genes that affect alcohol use disorders need to test loci and candidate genes against both phenotypes.

Do the Genetic or Environmental Determinants of Anxiety and Depression Change with Age? A Longitudinal Study of Australian Twins

Because the determinants of anxiety and depression in late adolescence and early adulthood may differ from those in later life, we investigated the temporal stability and magnitude of genetic and environmental correlates of symptoms of anxiety and depression across the life span. Data were collected from a population-based Australian sample of 4364 complete twin pairs and 777 singletons aged 20 to 96 years who were followed-up over three studies between 1980 and 1996. Each study contained the 14-item self-report DSSI/sAD scale which was used to measure recently experienced symptoms of anxiety and depression. Symptom scores were then divided and assigned to age intervals according to each subject's age at time of participation. We fitted genetic simplex models to take into account the longitudinal nature of the data. For male anxiety and depression, the best fitting simplex models comprised a single genetic innovation at age 20 which was transmitted, and explained genetic variation in anxiety and depression at ages 30, 40, 50 and 60. Most of the lifetime genetic variation in female anxiety and depression could also be explained by innovations at age 20 which were transmitted to all other ages; however, there were also smaller age-dependent genetic innovations at 30 for anxiety and at 40 and 70 for depression. Although the genetic determinants of anxiety and depression appear relatively stable across the life-span for males and females, there is some evidence to support additional mid-life and late age gene action in females for depression. The fact that mid-life onset for anxiety occurs one decade before depression is also consistent with a causal relationship (anxiety leading to depression) between these conditions. These findings have significance for large scale depression prevention projects.

Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities

Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community sample of 6,265 Australian twins (55% female) aged 25-36 who had completed an interview based on International Headache Society UHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of individuals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of individuals were negative for aura). Using the LCA classification, many more individuals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h(2) =0.40; 95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36; 95% CI, 0.22-0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine. (C) 2004 Wiley-Liss, Inc.

Genetic Epidemiology of Alcohol-Induced Blackouts

Background: Alcohol-induced blackouts (ie, periods of anterograde amnesia) have received limited recent research attention. Objective: To examine the genetic epidemiology of lifetime blackouts and having had 3 or more blackouts in a year, including analyses controlling for the frequency of intoxication. Design, Setting, and Participants: Members of the young adult Australian Twin Register, a volunteer twin panel born between January 1, 1964, and December 3 1, 1971, were initially registered with the panel as children by their parents between 1980 and 1982. They underwent structured psychiatric telephone inter-views from February 1996 through September 2000. The current sample contains 2324 monozygotic and dizygotic twin pairs (mean [SDI age 29.9 [2.5] years) for whom both twins' responses were coded for blackout questions and for frequency of intoxication. Main Outcome Measure: Data on lifetime blackouts and having had 3 or more blackouts in a year were collected within an examination of the genetic epidemiology of alcoholism. Results: A lifetime history of blackouts was reported by 39.3% of women and 52.4% of men; 11.4% of women and 20.9% of men reported having had 3 or more blackouts in a year. The heritability of lifetime blackouts was 52.5% and that of having had 3 or more blackouts in a year was 57.8%. Models that controlled for frequency of intoxication found evidence of substantial genetic contribution unique to risk for the blackouts and a significant component of genetic risk shared with frequency of intoxication. Conclusions: The finding of a substantial genetic contribution to liability for alcohol-induced blackouts including a component of genetic loading shared with frequency of intoxication may offer important additional avenues to investigate susceptibility to alcohol-related problems.

Defining nicotine dependence for genetic research: evidence from Australian twins

Background. Whether current criteria used to define nicotine dependence are informative for genetic research is an important empirical question. The authors used items of the DSM-IV and of the Heaviness of Smoking Index to characterize the nicotine dependence phenotype and to identify salient symptoms in a genetically informative community sample of Australian young adult female and mate twins. Method. Phenotypic and genetic factor analyses were performed on nine dependence symptoms (the seven DSM-IV substance dependence criteria and the two Heaviness of Smoking Index (HSI) items derived from the Fagerstrom Tolerance Questionnaire, time to first cigarette in the morning and number of cigarettes smoked per day). Phenotypic and genetic analyses were restricted to ever smokers. Results. Phenotypic nicotine dependence symptom covariation was best captured by two factors with a similar pattern of factor loadings for women and men. In genetic factor analysis item covariation was best captured by two genetic but one shared environmental factor for both women and men; however, item factor loadings differed by gender. All nicotine dependence symptoms were substantially heritable, except for the DSM-IV criterion of 'giving up or reducing important activities in order to smoke', which was weakly familial. Conclusions. The salient behavioral indices of nicotine dependence are similar for women and men. DSM-IV criteria of tolerance, withdrawal, and experiencing difficulty quitting and HSI items time to first cigarette in the morning and number of cigarettes smoked per day may represent the most highly heritable symptoms of nicotine dependence for both women and men.

Major Depressive Disorder, Suicidal Ideation, and Suicide Attempt in Twins Discordant for Cannabis Dependence and Early-Onset Cannabis Use

Background: Previous research has reported both a moderate degree of comorbidity between cannabis dependence and major depressive disorder (MDD) and that early-onset cannabis use is associated with increased risks for MDD. Objective: To examine whether associations between both lifetime cannabis dependence and early cannabis use and measures of MDD, suicidal ideation, and suicide attempt persist after controlling for genetic and/or shared environmental influences. Design: Cross-sectional survey of twin pairs discordant for lifetime cannabis dependence and those discordant for early cannabis use. Setting: General population sample of twins (median age, 30 years). Participants: Two hundred seventy-seven same-sex twin pairs discordant for cannabis dependence and 311 pairs discordant for early-onset cannabis use (before age 17 years). Main Outcome Measures: Self-report measures of DSM-IV-defined lifetime MDD, suicidal ideation, and suicide attempt. Results: Individuals who were cannabis dependent had odds of suicidal ideation and suicide attempt that were 2.5 to 2.9 times higher than those of their non-cannabis-dependent co-twin. Additionally, cannabis dependence was associated with elevated risks of MDD in dizygotic but not in monozygotic twins. Those who initiated cannabis use before age 17 years had elevated rates of subsequent suicide attempt (odds ratio, 3.5 [95% confidence interval, 1.4-8.6]) but not of MDD or suicidal ideation. Early MDD and suicidal ideation were significantly associated with subsequent risks of cannabis dependence in discordant dizygotic pairs but not in discordant monozygotic pairs. Conclusions: Comorbidity between cannabis dependence and MDD likely arises through shared genetic and environmental vulnerabilities predisposing to both outcomes. In contrast, associations between cannabis dependence and suicidal behaviors cannot be entirely explained by common predisposing genetic and/or shared environmental predispositions. Previously reported associations between early-onset cannabis use and subsequent MDD likely reflect shared genetic and environmental vulnerabilities, although it remains possible that early-onset cannabis use may predispose to suicide attempt.

Genetic effects on alcohol dependence risk: re-evaluating the importance of psychiatric and other heritable risk factors

Background. Genetic influences have been shown to play a major role in determining the risk of alcohol dependence (AD) in both women and men; however, little attention has been directed to identifying the major sources of genetic variation in AD risk. Method. Diagnostic telephone interview data from young adult Australian twin pairs born between 1964 and 1971 were analyzed. Cox regression models were fitted to interview data from a total of 2708 complete twin pairs (690 MZ female, 485 MZ male, 500 DZ female, 384 DZ male, and 649 DZ female/male pairs). Structural equation models were fitted to determine the extent of residual genetic and environmental influences on AD risk while controlling for effects of sociodemographic and psychiatric predictors on risk. Results. Risk of AD was increased in males, in Roman Catholics, in those reporting a history of major depression, social anxiety problems, and conduct disorder, or (in females only) a history of suicide attempt and childhood sexual abuse; but was decreased in those reporting Baptist, Methodist, or Orthodox religion, in those who reported weekly church attendance, and in university-educated males. After allowing for the effects of sociodemographic and psychiatric predictors, 47 % (95 % CI 28-55) of the residual variance in alcoholism risk was attributable to additive genetic effects, 0 % (95 % CI 0-14) to shared environmental factors, and 53 % (95 % CI 45-63) to non-shared environmental influences. Conclusions. Controlling for other risk factors, substantial residual heritability of AD was observed, suggesting that psychiatric and other risk factors play a minor role in the inheritance of AD.

Energy as an entanglement witness for quantum many-body systems

We investigate quantum many-body systems where all low-energy states are entangled. As a tool for quantifying such systems, we introduce the concept of the entanglement gap, which is the difference in energy between the ground-state energy and the minimum energy that a separable (unentangled) state may attain. If the energy of the system lies within the entanglement gap, the state of the system is guaranteed to be entangled. We find Hamiltonians that have the largest possible entanglement gap; for a system consisting of two interacting spin-1/2 subsystems, the Heisenberg antiferromagnet is one such example. We also introduce a related concept, the entanglement-gap temperature: the temperature below which the thermal state is certainly entangled, as witnessed by its energy. We give an example of a bipartite Hamiltonian with an arbitrarily high entanglement-gap temperature for fixed total energy range. For bipartite spin lattices we prove a theorem demonstrating that the entanglement gap necessarily decreases as the coordination number is increased. We investigate frustrated lattices and quantum phase transitions as physical phenomena that affect the entanglement gap.

Genomewide significant linkage to migrainous Hheadache on chromosome 5q21

Familial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23-90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs ( 130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine.

Detecting multipartite entanglement

We discuss the problem of determining whether the state of several quantum mechanical subsystems is entangled. As in previous work on two subsystems we introduce a procedure for checking separability that is based on finding state extensions with appropriate properties and may be implemented as a semidefinite program. The main result of this work is to show that there is a series of tests of this kind such that if a multiparty state is entangled this will eventually be detected by one of the tests. The procedure also provides a means of constructing entanglement witnesses that could in principle be measured in order to demonstrate that the state is entangled.

Genetic analyses of DSM-IV nicotine withdrawal in adult twins

Background. We examined whether there are genetic influences on nicotine withdrawal. and whether there are genetic factors specific to nicotine withdrawal, after controlling for factors responsible for risk of progression beyond experimentation with cigarettes and for quantity smoked (average number of cigarettes per day at peak lifetime use). Method. Epidemiologic and genetic analyses were conducted using telephone diagnostic interview data from Young adult Australian twins reporting any cigarette use (3026 women. 2553 men: mean age 30 years). Results. Genetic analysis of the eight symptoms of DSM-IV nicotine withdrawal suggests heritability is intermediate for most symptoms (26-43%). and Similar in men and women. The exceptions were depressed mood upon withdrawal. which had stronger additive genetic influences in men (53%) compared to worrien (29%). and decreased heart rate. which had low heritability (9%). Although prevalence rates were substantlally lower for DSM-IV nicotine withdrawal syndrome (15-9%), which requires impairment. than for the DSM-IV nicotine dependence withdrawal criterion (43.6%), heritability was similar for both measures: as high as 47%. Genetic modeling of smoking more than 1 or 2 cigarettes lifetime ('progression'). qualtity smoked and nicotine withdrawal found significant genetic overlap across all three components of nicotine use/dependence (genetic correlations = 0.53-0.76). Controlling for factors associated with risk of cigarette smoking beyond experimentation and quantity smoked, evidence for genetic influences specific to nicotine withdrawal (up to 23% of total variance) remained. Conclusions. Our results suggest that at least some individuals become 'hooked' or progress in the smoking habit, in part, because of it vulnerability to nicotine withdrawal.

Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design

Background. Children of alcoholics are significantly more likely to experience high-risk environmental exposures, including prenatal substance exposure, and are more likely to exhibit externalizing problems [e.g. attention deficit hyperactivity disorder (ADHD)]. While there is evidence that genetic influences and prenatal nicotine and/or alcohol exposure play separate roles in determining risk of ADHD, little has been done on determining the joint roles that genetic risk associated with maternal alcohol use disorder (AUD) and prenatal risk factors play in determining risk of ADHD. Method. Using a children-of-twins design, diagnostic telephone interview data from high-risk families (female monozygotic and dizygotic twins concordant or discordant for AUD as parents) and control families targeted from a large Australian twin cohort were analyzed using logistic regression models. Results. Offspring of twins with a history of AUD, as well as offspring of non-AUD monozygotic twins whose co-twin had AUD, were significantly more likely to exhibit ADHD than offspring of controls. This pattern is consistent with a genetic explanation for the association between maternal AUD and increased offspring risk of ADHD. Adjustment for prenatal smoking, which remained significantly predictive, did not remove the significant genetic association between maternal AUD and offspring ADHD. Conclusions. While maternal smoking during pregnancy probably contributes to the association between maternal AUD and offspring ADHD risk, the evidence for a significant genetic correlation suggests: (i) pleiotropic genetic effects, with some genes that influence risk of AUD also influencing vulnerability to ADHD; or (ii) ADHD is a direct risk-factor for AUD.

A genetically informed study of the processes underlying the association between parental marital instability and offspring adjustment

Parental divorce is associated with problematic offspring adjustment, but the relation may be due to shared genetic or environmental factors. One way to test for these confounds is to study offspring of twins discordant for divorce. The current analyses used this design to separate the mechanisms responsible for the association between parental divorce, experienced either before or after the age of 16, and offspring well-being. The results were consistent with a causal role of divorce in earlier initiation of sexual intercourse and emotional difficulties, in addition to a greater probability of educational problems, depressed mood, and suicidal ideation. In contrast, the increased risk for cohabitation and earlier initiation of drug use was explained by selection factors, including genetic confounds.