Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores

Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome‐wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention‐deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM‐IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross‐disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention‐deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women.     

Substance Use Disorders and Adoption: Findings from a National Sample

Background

Prior research has shown that adoptees have a higher rate of substance use disorders (SUDs) than nonadoptees. But these findings have not been verified with a population-based sample of adult adoptees in the United States. Also, no previous adoption study has measured the prevalence of each specific substance use disorder (SUD). We aimed to compare lifetime prevalence rates and odds ratios of SUDs in adopted and nonadopted adults.

Methods and Findings

The data come from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). The main outcome measure was the prevalence of lifetime SUDs in adopted (n = 378) and nonadopted adults (n = 42503). Adoptees and nonadoptees were compared to estimate the odds of lifetime SUDs using logistic regression analysis. Adoptees had higher prevalence rates of lifetime SUDs than nonadoptees. Overall, adoptees had a 1.87-fold increase (adjusted odds ratio [AOR] 1.87, 95% CI 1.51–2.31) in the odds of any lifetime SUD compared to nonadoptees. For each SUD, adoptees had higher odds for alcohol abuse/dependence (AOR 1.84), nicotine dependence (AOR 1.78), cannabis abuse/dependence (AOR 1.77), cocaine abuse/dependence (AOR 2.54), amphetamine abuse/dependence (AOR 3.14), hallucinogen abuse/dependence (AOR 2.85), opioid abuse/dependence (AOR 2.21), and other drug abuse/dependence (AOR 2.87) compared to nonadoptees. This study also identified two adoption-specific risk factors (Hispanic, never married) associated with any lifetime SUD.

Conclusions

This study demonstrated an increased risk of lifetime SUDs in adopted adults. The findings can be useful for clinicians and policy makers to provide education, prevention, and support for adoptees and their families.     

iPSCs: induced back to controversy

Several recent reports (Mayshar et?al., 2010; Laurent et?al., 2011; Lister et?al., 2011; Gore et?al., 2011; Hussein et?al., 2011) uncover genetic and epigenetic alterations in induced pluripotent stem cells, stimulating debate about their future. However, will these important findings really impact what we hope to gain?     

Robust generation of hepatocyte-like cells from human embryonic stem cell populations

Despite progress in modelling human drug toxicity, many compounds fail during clinical trials due to unpredicted side effects. The cost of clinical studies are substantial, therefore it is essential that more predictive toxicology screens are developed and deployed early on in drug development (Greenhough et al 2010). Human hepatocytes represent the current gold standard model for evaluating drug toxicity, but are a limited resource that exhibit variable function. Therefore, the use of immortalised cell lines and animal tissue models are routinely employed due to their abundance. While both sources are informative, they are limited by poor function, species variability and/or instability in culture (Dalgetty et al 2009). Pluripotent stem cells (PSCs) are an attractive alternative source of human hepatocyte like cells (HLCs) (Medine et al 2010). PSCs are capable of self renewal and differentiation to all somatic cell types found in the adult and thereby represent a potentially inexhaustible source of differentiated cells. We have developed a procedure that is simple, highly efficient, amenable to automation and yields functional human HLCs (Hay et al 2008 ; Fletcher et al 2008 ; Hannoun et al 2010 ; Payne et al 2011 and Hay et al 2011). We believe our technology will lead to the scalable production of HLCs for drug discovery, disease modeling, the construction of extra-corporeal devices and possibly cell based transplantation therapies.     

Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well‐suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit‐wide restructuring of local and long‐range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine‐dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place.     

Integration of evidence across human and model organism studies: A meeting report

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration—particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.     

The Global Burden of Mental,Neurological and Substance Use Disorders: An Analysis from the Global Burden of Disease Study 2010

BackgroundThe Global Burden of Disease Study 2010 (GBD 2010), estimated that a substantial proportion of the world’s disease burden came from mental, neurological and substance use disorders. In this paper, we used GBD 2010 data to investigate time, year, region and age specific trends in burden due to mental, neurological and substance use disorders.MethodFor each disorder, prevalence data were assembled from systematic literature reviews. DisMod-MR, a Bayesian meta-regression tool, was used to model prevalence by country, region, age, sex and year. Prevalence data were combined with disability weights derived from survey data to estimate years lived with disability (YLDs). Years lost to premature mortality (YLLs) were estimated by multiplying deaths occurring as a result of a given disorder by the reference standard life expectancy at the age death occurred. Disability-adjusted life years (DALYs) were computed as the sum of YLDs and YLLs.ResultsIn 2010, mental, neurological and substance use disorders accounted for 10.4% of global DALYs, 2.3% of global YLLs and, 28.5% of global YLDs, making them the leading cause of YLDs. Mental disorders accounted for the largest proportion of DALYs (56.7%), followed by neurological disorders (28.6%) and substance use disorders (14.7%). DALYs peaked in early adulthood for mental and substance use disorders but were more consistent across age for neurological disorders. Females accounted for more DALYs in all mental and neurological disorders, except for mental disorders occurring in childhood, schizophrenia, substance use disorders, Parkinson’s disease and epilepsy where males accounted for more DALYs. Overall DALYs were highest in Eastern Europe/Central Asia and lowest in East Asia/the Pacific.ConclusionMental, neurological and substance use disorders contribute to a significant proportion of disease burden. Health systems can respond by implementing established, cost effective interventions, or by supporting the research necessary to develop better prevention and treatment options.     

Ephecting excitatory synapse development

Alterations in synapse number and morphology are associated with devastating psychiatric and neurologic disorders. In this issue of Cell, Margolis et?al. (2010) show that the RhoA-guanine exchange factor (GEF) Ephexin5 limits the numbers of excitatory synapses that neurons receive, thus identifying a new mechanism controlling synaptogenesis.     

Unraveling epigenetic landscapes: the enigma of enhancers

In recent publications in Nature and PNAS, Rada-Iglesias et?al. (2010) and Creyghton et?al. (2010) have uncovered unique chromatin signatures of developmental enhancers marking active, primed, or silent genes in human and mouse embryonic stem cells.     

The special delivery of a tail-anchored protein: why it pays to use a dedicated courier

The membrane-spanning C-terminal regions in tail-anchored proteins must be recognized and delivered posttranslationally to the endoplasmic reticulum or mitochondrial membrane. A paper in this issue of Molecular Cell (Wang et?al., 2010) and another recent report (Mariappan et?al., 2010) delineate early steps in this pathway.     

Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli

Learning to fear danger in the environment is essential to survival, but dysregulation of the fear system is at the core of many anxiety disorders. As a consequence, a great interest has emerged in developing strategies for suppressing fear memories in maladaptive cases. Recent research has focused in the process of reconsolidation where memories become labile after being retrieved. In a behavioral manipulation, Schiller et al., (2010) reported that extinction training, administrated during memory reconsolidation, could erase fear responses. The implications of this study are crucial for the possible treatment of anxiety disorders without the administration of drugs. However, attempts to replicate this effect by other groups have been so far unsuccessful. We sought out to reproduce Schiller et al., (2010) findings in a different fear conditioning paradigm based on auditory aversive stimuli instead of electric shock. Following a within-subject design, participants were conditioned to two different sounds and skin conductance response (SCR) was recorded as a measure of fear. Our results demonstrated that only the conditioned stimulus that was reminded 10 minutes before extinction training did not reinstate a fear response after a reminder trial consisting of the presentation of the unconditioned stimuli. For the first time, we replicated Schiller et al., (2010) behavioral manipulation and extended it to an auditory fear conditioning paradigm.     

New ways to make old walls: bacterial surprises

Two papers in this issue of Cell (Paradis-Bleau et?al., 2010 and Typas et?al., 2010) report that the lipoproteins LpoA and LpoB are required for the synthesis of cell walls in Escherichia coli. Attached to the bacterial outer membrane, these new cell wall components regulate penicillin-binding proteins located at the inner membrane.     

Excess Mortality in Patients with Severe Mental Disorders in 1996-2010 in Finland

Unselected population-based nationwide studies on the excess mortality of individuals with severe mental disorders are scarce with regard to several important causes of death. Using comprehensive register data, we set out to examine excess mortality and its trends among patients with severe mental disorders compared to the total population. Patients aged 25–74 and hospitalised with severe mental disorders in 1990–2010 in Finland were identified using the national hospital discharge register and linked individually to population register data on mortality and demographics. We studied mortality in the period 1996–2010 among patients with psychotic disorders, psychoactive substance use disorders, and mood disorders by several causes of death. In addition to all-cause mortality, we examined mortality amenable to health care interventions, ischaemic heart disease mortality, disease mortality, and alcohol-related mortality. Patients with severe mental disorders had a clearly higher mortality rate than the total population throughout the study period regardless of cause of death, with the exception of alcohol-related mortality among male patients with psychotic disorders without comorbidity with substance use disorders. The all-cause mortality rate ratio of patients with psychotic disorders compared to the total population was 3.48 (95% confidence interval 2.98–4.06) among men and 3.75 (95% CI 3.08–4.55) among women in the period 2008–10. The corresponding rate ratio of patients with psychoactive substance use disorders was 5.33 (95% CI 4.87–5.82) among men and 7.54 (95% CI 6.30–9.03) among women. Overall, the mortality of the total population and patients with severe mental disorders decreased between 1996 and 2010. However, the mortality rate ratio of patients with psychotic disorders and patients with psychoactive substance use disorders compared to the total population increased in general during the study period. Exceptions were alcohol-related mortality among patients with psychoactive substance use disorders and female patients with psychotic disorders, as well as amenable mortality among male patients with psychotic disorders. The mortality rate ratio of persons with mood disorders compared to the total population decreased. The markedly high mortality amenable to health care intervention among patients with severe mental disorders found in our study suggests indirectly that they may receive poorer quality somatic care. The results highlight the challenges in co-ordinating mental and somatic health services.     

Substance use disorders: a comprehensive update of classification,epidemiology, neurobiology,clinical aspects,treatment and prevention

Substance use disorders (SUDs) are highly prevalent and exact a large toll on individuals’ health, well-being, and social functioning. Long-lasting changes in brain networks involved in reward, executive function, stress reactivity, mood, and self-awareness underlie the intense drive to consume substances and the inability to control this urge in a person who suffers from addiction (moderate or severe SUD). Biological (including genetics and developmental life stages) and social (including adverse childhood experiences) determinants of health are recognized factors that contribute to vulnerability for or resilience against developing a SUD. Consequently, prevention strategies that target social risk factors can improve outcomes and, when deployed in childhood and adolescence, can decrease the risk for these disorders. SUDs are treatable, and evidence of clinically significant benefit exists for medications (in opioid, nicotine and alcohol use disorders), behavioral therapies (in all SUDs), and neuromodulation (in nicotine use disorder). Treatment of SUDs should be considered within the context of a Chronic Care Model, with the intensity of intervention adjusted to the severity of the disorder and with the concomitant treatment of comorbid psychiatric and physical conditions. Involvement of health care providers in detection and management of SUDs, including referral of severe cases to specialized care, offers sustainable models of care that can be further expanded with the use of telehealth. Despite advances in our understanding and management of SUDs, individuals with these conditions continue to be stigmatized and, in some countries, incarcerated, highlighting the need to dismantle policies that perpetuate their criminalization and instead develop policies to ensure support and access to prevention and treatment.     

Stem cells and osteoporosis therapy

Skeletal remodeling requires recruitment of osteoblast precursors, in the form of MSCs, to the bone surface. In this issue of Cell Stem Cell, Wu et?al. (2010) demonstrate that this event is mediated by osteoclastic mobilization of active transforming growth factor β1, which is inhibited by a common antiosteoporosis drug.     

Modeling Rett syndrome with stem cells

The discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) raised the exciting possibility of modeling diseases with patient-specific cells. Marchetto et?al. (2010) now use iPSC technology to generate, characterize, and treat an in?vitro model for the autism spectrum disorder Rett syndrome.     

Shining a light on germinal center B cells

The mechanisms of B cell selection in lymphoid tissues are poorly understood. In this issue, Victora et?al. (2010) use imaging of photoactivatable green fluorescent protein to define the movements of B?cells in germinal centers and provide evidence that antibody affinity maturation is driven by competition for T?cell help.     

Posterior reversible encephalopathy syndrome associated with nephrotic syndrome

Kabicek and colleagues described a case of nephritic-syndrome-associated posterior reversible encephalopathy syndrome (PRES) (Kabicek, et al. 2010). This adds to the accumulating evidence that PRES can be associated with disorders other than hypertension. However, we wonder how the authors would explain the neuroimaging findings unsuggestive of vasogenic oedema. PRES (also named reversible posterior leukoencephalopathy syndrome, RPLS) represents a clinicoradiological syndrome characterized by vasogenic oedema as revealed by apparent diffusion coefficient (ADC) map of diffusion-weighted imaging (DWI) (Bartynski, 2008). The pathogenesis of PRES has been suggested to be autoregulation failure and endothelial dysfunction (Sharma, et al.). ...