Liability to substance use disorders: 2. A measurement approach

Liabilities to complex disorders, discussed in the accompanying paper, present difficulties in measurement related to the arbitrariness of diagnostic threshold definitions and problems with discrimination between trait values, especially within the 'normal' individuals. The inability to quantitatively estimate the risk for a disorder, such as substance use disorders (SUD), is an obstacle for studying etiological (e.g. genetic) mechanisms and developing efficient prevention and treatment measures. Based on the concept of common liability to SUD, this paper delineates an application of the longitudinal family/high-risk design and item response theory to the development of a continuous index of liability. The method has been tested in both simulation study and empirical data. The approach described affords the opportunity to quantitatively estimate the risk for SUD at an early age and before any drug exposure. This method is also applicable to measuring liabilities to other complex disorders, especially those with relatively late onset.     

Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies

CONTEXT: There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used. OBJECTIVE: To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data. DATA SOURCES: We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches. STUDY SELECTION: Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment. DATA SYNTHESIS: By using a multigroup twin model, we found evidence for substantial additive genetic effects-the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia-joint estimate, 11% (95% confidence interval, 3%-19%). CONCLUSIONS: Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.     

A population-based twin study of the relationship between neuroticism and internalizing disorders

OBJECTIVE: The anxiety and depressive disorders exhibit high levels of lifetime comorbidity with one another. The authors examined how genetic and environmental factors shared by the personality trait neuroticism and seven internalizing disorders may help explain this comorbidity. METHOD: Lifetime major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, situational phobia, and neuroticism were assessed in over 9,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Multivariate structural equation models were used to decompose the correlations between these phenotypes into genetic and environmental components, allowing for sex-specific factors. RESULTS: Genetic factors shared with neuroticism accounted for between one-third and one-half of the genetic risk across the internalizing disorders. When nonsignificant gender differences were removed from the models, the genetic correlations between neuroticism and each disorder were high, while individual-specific environmental correlations were substantially lower. In addition, the authors could identify a neuroticism-independent genetic factor that significantly increased risk for major depression, generalized anxiety disorder, and panic disorder. CONCLUSIONS: There is substantial, but not complete, overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability across the internalizing disorders, helping to explain the high rates of comorbidity among the latter. This may have important implications for identifying the susceptibility genes for these conditions.     

Physical maturation, peer environment, and the ontogenesis of substance use disorders

The risk for substance use disorders (SUD) is transmissible between generations via both genetic and environmental mechanisms. One path that is hypothesized to mediate this transmission and include both types of mechanisms is through faster physiological maturation, leading to suboptimal self-regulation, affiliation with deviant peers, and higher risk for conduct disorder (CD). Extending prior research, this hypothesis was tested in a longitudinal study. A sample of 478 males whose fathers were affected with SUD or psychiatrically normal was assessed prospectively at ages from 9-13 to 17-20. The DSM-III-R diagnoses were obtained using standard methodology. Blood testosterone was assayed by radioimmunoassay, and Tanner staging was used to evaluate sexual maturation. Peer deviance was evaluated by the Peer Delinquency Scale. Correlation and path analysis, Cox proportional hazard regression, and growth curve modeling were used to determine the relationships between the variables. The data support the hypothesis that parental SUD liability influences the rate of physiological maturation in offspring, which in turn is related to affiliation with deviant peers and an elevated rate of the development of CD and SUD.     

Determinants of risk behavior for human immunodeficiency virus/acquired immunodeficiency syndrome in people with severe mental illness.

We examined the prevalence and correlates of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) risk behaviors in a large sample of severely mentally ill (SMI) patients. Risk levels were correlated with demographic factors, diagnosis, symptom severity, trauma history, post-traumatic stress disorder (PTSD), substance use disorder (SUD), and sexual orientation. SMI clients from urban and rural settings (N = 275) were assessed regarding HIV/AIDS risk behaviors, and hypothesized risk factors. Patients exhibited substantial levels of risky behavior, particularly sexual risk. Correlates of increased risk included SUD, trauma, male homosexual orientation, younger age, and symptom severity. Structural equation modeling identified SUD and sexual orientation as the primary determinants of both drug and sexual risk behavior. We conclude that specific illness related variables appear to have less impact on risk behavior among people with SMI than previously hypothesized. Substance abuse prevention and treatment may be the most effective means of reducing HIV risk in this population.     

Attention-deficit/hyperactivity disorder and the substance use disorders: the nature of the relationship, subtypes at risk, and treatment issues.

There is a strong literature supporting a relationship between ADHD and SUD. Clearly, ADHD adolescents with conduct or bipolar disorder as partof their clinical picture are at the highest risk for SUD. ADHD without comorbidity appears to confer an intermediate risk factor for SUD that appears to manifest in young adults and college students. Both family genetic and self-medication influences may be operational in the development and continuation of SUD in ADHD subjects: however, systematic data are lacking. Patients with ADHD and SUD require multi-modal intervention incorporating addiction and mental health treatment. Pharmacotherapy in individuals with ADHD and SUD needs to take into consideration abuse liability, potential drug interactions, and compliance concerns.Although the existing literature has provided important information on the relationship of ADHD and SUD, it also points to a number of areas in need of further study. The mechanism by which untreated ADHD leads toSUD and the risk reduction of ADHD treatment on later SUD, needs to be understood better. The influence of adequateness of treatment of ADHD on later SUD needs to be delineated. Given the prevalence and major morbidity and impairment caused by SUD and ADHD. prevention and treatment strategies for these patients need to be developed and evaluated further.     

A population-based twin study of major depression in women. The impact of varying definitions of illness.

Although depression aggregates in families, the degree to which this aggregation results from genetic vs environmental factors remains uncertain. We examined this question in 1033 female-female twin pairs from a population-based registry. Both members of each twin pair were "blindly" assessed by structured psychiatric interview. Nine commonly used definitions of major depression, which produced life-time prevalence rates ranging from 12% to 33%, were examined. For all definitions, the results of model fitting to twin correlations suggested that the liability to depression results from genetic factors and environmental experiences unique to the individual. For seven of the definitions, the estimated heritability of liability was similar, ranging from 33% to 45%. For the two definitions that included only primary cases of depression, the heritability was lower (21% to 24%). The results document that in women (1) genetic factors play a substantial, but not overwhelming, role in the cause of depression; (2) the tendency for depression to aggregate in families results largely from shared genetic and not from shared environmental factors; (3) except for definitions that exclude secondary cases, the magnitude of genetic influence is similar in broadly and narrowly defined forms of major depression; and (4) most environmental experiences of causative importance for depression are those not shared by members of an adult twin pair.     

Gender differences in binge-eating: a population-based twin study

OBJECTIVE: To assess whether genetic and environmental effects on liability to binge-eating (BE) are of equal importance for males and females and whether the same genetic risk factors predispose to BE in the two sexes. METHOD: Questionnaire data on 8045 same sex and opposite sex twins, aged 19-31 years, from a population-based Norwegian registry, was used to estimate the relative contribution of genetic and environmental factors to liability for BE utilizing structural equation modeling. RESULTS: In the best-fitting model, the magnitude of genetic and environmental effects on BE was the same for males and females. Heritability was 51%. The correlation between genetic risk factors in men and women was estimated to be +0.57. CONCLUSION: Binge-eating appears to be equally heritable in males and females. Although the majority of the genetic risk factors are shared between the sexes, there may exist gender-specific genetic effects on liability.     

White matter pathology -- an endophenotype for bipolar disorder?

ABSTRACT: BACKGROUND: Neuroimaging investigations of white matter abnormalities in subjects at genetic risk for bipolar disorders (BD) potentially predating the onset of BD offer several advantages. They are not confounded by the presence of illness duration or previous treatment with medication and may ultimately inform evaluation of risk for subsequent development of BD and subsequent therapeutic intervention. DISCUSSION: Although a number of imaging studies in subjects at genetic risk for BD are available the results are conflicting and no reliable structural markers of genetic liability to bipolar disorders have been proposed. We debate that white matter pathology may be central to the genetic risk to develop BD. Thus, white matter abnormalities detectable in HR subjects but not in controls may reflect genetically driven trait markers. Similar abnormalities may be also evident both in the HR and in BD, suggesting the possibility of genetic risk factors shared by both groups. Conversely, white matter alterations observed in BD patients but not in HR and controls can be interpreted as state markers. SUMMARY: We suggest that white matter alterations may represent endophenotypes and neurobiological markers intermediate between the underlying susceptibility genes and the clinical expression of BD.     

A twin study of genetic relationships between psychotic symptoms

OBJECTIVE: Biometrical model fitting was applied to clinical data from twins to investigate whether operationally defined schizophrenic, schizoaffective, and manic syndromes share genetic risk factors. METHOD: Seventy-seven monozygotic and 89 same-sex dizygotic twin pairs in which the proband met the Research Diagnostic Criteria (RDC) for lifetime-ever schizophrenic, schizoaffective, or manic syndrome were ascertained from the Maudsley Twin Register in London. The syndromes were defined non-hierarchically. Correlations in liability were calculated for each syndrome in the monozygotic and dizygotic pairs and across the three pairings of schizophrenic-manic, schizophrenic-schizoaffective, and schizoaffective-manic syndromes both within probands and within pairs. For the three syndromes considered together, an independent pathway model was fitted. RESULTS: The model fitting showed significant genetic correlations between all three syndromes. There was evidence of both common and syndrome-specific genetic contributions to the variance in liability to the schizophrenic and manic syndromes, but the genetic liability to the schizoaffective syndrome was entirely shared in common with the other two syndromes. In contrast, environmental liability to the schizoaffective syndrome was not shared with the other syndromes. CONCLUSIONS: If diagnostic hierarchies are relaxed, there is a degree of overlap in the genes contributing to RDC schizophrenic, schizoaffective, and manic syndromes. Supplementing the traditional approach of assigning a single main lifetime diagnosis with information on within-person comorbidity of psychotic syndromes may provide valuable information about the familial aggregation of psychotic symptoms.     

Sex differences in risk factors for suicidality among Japanese substance use disorder patients: Association with age, types of abused substances, and depression

Aim: The aim of this study was to identify risk factors for suicide in Japanese substance use disorder (SUD) patients, adjusting for age and sex, and to examine sex differences in suicide risk among these patients. Methods: A self-reporting questionnaire on age, sex, types of abused substances, current depression, and suicidality was administered to 1420 SUD patients who consecutively visited seven hospitals specializing in SUD treatment during the month of December 2009. Unadjusted/adjusted odds ratios of factors associated with suicidality were calculated for each sex. Results: The multivariate analysis using the total sample identified younger age, female sex, and current depression as risk factors for severe suicidality in SUD patients. The multivariate analysis by each sex demonstrated that younger age and current depression were associated with severe suicidality in male SUD patients. Only current depression was associated with severe suicidality in female patients. Conclusion: Current depression is a risk factor for suicide in SUD patients common in both Western countries and Japan, although in Japanese SUD patients both younger age and female sex were more closely associated with severe suicidality than aspects of SUD. Additionally, young male SUD patients are speculated to have psychosocial features associated with suicidality in common with female SUD patients.     

Major depression and generalized anxiety disorder. Same genes, (partly) different environments?

Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences.     

The genetics of major depressive disorder

There is consistent evidence that major depression is familial and population-based twin studies as well as hospital register-based twin studies find substantial heritability. However, there is also a large proportion of variation in liability left to be explained by nongenetic factors. Although there seems little doubt that life events play a role in precipitating depression, studies that have attempted to examine familial liability along with social adversity find that environmental measures tend to be contaminated by genetic effects. Thus, the tendency to experience (or report) life events appears to be influenced by shared family environment, and for certain types of events there is a genetic component. The molecular genetic basis of liability to depression is an under-researched area, but some candidate gene studies show potentially promising results. Systematic mapping studies aiming to cover the entire genome are currently being launched.     

The heritability of bipolar affective disorder and the genetic relationship to unipolar depression

BACKGROUND: Twin studies of bipolar affective disorder (BPD) have either been small or have not used explicit diagnostic criteria. There has been little use of genetic model fitting and no analyses to explore the etiological overlap with unipolar depression (UPD). METHODS: Sixty-seven twin pairs, 30 monozygotic and 37 dizygotic, in which the proband had BPD were ascertained, and lifetime diagnoses were made using DSM-IV criteria. Univariate models were applied to estimate the contribution of additive genetic and environmental effects. Bipolar data were then combined with those from 68 monozygotic and 109 dizygotic pairs in which the proband had UPD. Two models were explored: a classic 2-threshold approach, in which BPD and UPD occupy the same continuum of liability but differ in severity, and a correlated liability model of mania and depression. RESULTS: Heritability of BPD was estimated at 85% (95% confidence interval [CI], 0.73-0.93) using narrow concordance and 89% (95% CI, 0.61-1.0) using broad concordance, with no shared environmental effects detected. A 2-threshold model was an unsatisfactory fit. Fitting a correlated liability model revealed a genetic correlation of 0.65 (95% CI, 0.58-0.75) between mania and depression and a correlation of 0.59 (95% CI, 0.15-0.84) for nonfamilial environment. Approximately 71% of the genetic variance for mania was not shared with depression. CONCLUSIONS: As defined by the DSM-IV, BPD is highly heritable. There are substantial genetic and nonshared environmental correlations between mania and depression, but most of the genetic variance in liability to mania is specific to the manic syndrome.     

The relationship between avoidant personality disorder and social phobia: a population-based twin study

OBJECTIVE: The purpose of this study was to determine the sources of comorbidity for social phobia and dimensional representations of avoidant personality disorder by estimating to what extent the two disorders are influenced by common genetic and shared or unique environmental factors versus the extent to which these factors are specific to each disorder. METHOD: Young adult female-female twin pairs (N=1,427) from the Norwegian Institute of Public Health Twin Panel were assessed at personal interview for avoidant personality disorder and social phobia using the Structured Interview for DSM-IV Personality and the Composite International Diagnostic Interview. Bivariate Cholesky models were fitted using the Mx statistical program. RESULTS: The best-fitting model included additive genetic and unique environmental factors only. Avoidant personality disorder and social phobia were influenced by the same genetic factors, whereas the environmental factors influencing the two disorders were uncorrelated. CONCLUSIONS: Within the limits of statistical power, these results suggest that there is a common genetic vulnerability to avoidant personality disorder and social phobia in women. An individual with high genetic liability will develop avoidant personality disorder versus social phobia entirely as a result of the environmental risk factors unique to each disorder. The results are in accordance with the hypothesis that psychobiological dimensions span the axis I and axis II disorders.     

The Perception of Substance Use Disorder Among Clinicians,Caregivers and Family Members of Individuals With Intellectual and Developmental Disabilities

Introduction: Substance use disorders (SUD) are common among individuals with intellectual and developmental disorders (IDD). The quality of care individuals with these conditions receive can be affected by perceptions and attributions of SUD among clinicians, professional caregivers, and family members. The aim of this study was to explore such perceptions and attributions. Method: We conducted a web-based survey using snowball sampling. The Illness Perception Questionnaire Revised (IPQ-R) was used to assess SUD perceptions and attributions. Our sample consisted of 88 clinicians (53.3%), 58 caregivers (35.2%), and 19 adult family members (11.5%), mostly from the United States (73.3%). Results: Respondents—especially clinicians—indicated having a clear concept of the nature of SUD. They recognize that SUD has major consequences for the client, but are positive about the influence both the client and treatment can have on its course and outcome. SUD is attributed to psychological factors (especially so by clinicians and professional caregivers), including stress and worries, and personality, as well as to general risk factors, including hereditary and behavioral factors. Conclusion: According to our respondents, SUD is a serious condition with major consequences, and a variety of potential causes. Given the high prevalence of substance use in the ID population, this calls for more attention for identification, prevention, and treatment of SUD. This includes improving access to SUD treatment adapted to the needs of individuals with IDD, improving coping and emotional skills, and promoting a fulfilling life with adequate social support.     

Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population‐based family twin study of migraine without aura

Migraine without aura (MO) is a multifactorial disorder. Expression of a disorder with multifactorial inheritance depends on the genetic liability and on environmental factors. A high liability is reflected by a high frequency of affected relatives. We have previously shown that monozygotic (MZ) twin pairs have a significant higher concordance of MO than dizygotic twin pairs. The incomplete concordance among MZ twin pairs may be due to a lower genetic liability among discordant than concordant MZ twin pairs. The present study analysed the genetic liability in MZ twin pairs concordant and discordant for MO by the population-relative risk of MO among parents and siblings. The twin pairs were from the population-based Danish Twin Register. First-degree relatives of 29 concordant and 34 discordant MZ twin pairs were blindly telephone interviewed by a physician. The participation rate of the eligible first-degree relatives was 96%. The population-relative risk of MO among parents and siblings was 2.73 (2.39-3.06) in concordant and 2.37 (2.03-2.71) in discordant MZ twin pairs. The relative risk of MO was significantly higher in female first-degree relatives of concordant than of discordant MZ male and female twin pairs. An opposite effect was observed in male first-degree relatives, although this was not significant for male first-degree relatives of female MZ twin pairs. The present study found no statistically significant difference in genetic liability to MO among concordant and discordant MZ twin pairs. However, a difference in genetic liability among MZ and DZ twin pairs is anticipated to be small. Thus, it may be possible to show the effect in a larger study population or by investigating a more frequent trait than MO.     

Attention-deficit/hyperactivity disorder and early-onset substance use disorders

In recent years, there has been an increased recognition of the common comorbidity of attention-deficit/ hyperactivity disorder (ADHD) and substance use disorder (SUD) among adolescents and adults. ADHD can be an important factor in the pathogenesis and maintenance of SUD; moreover, retrospective studies suggest that treating ADHD during childhood may prevent the development of SUD. In addition, treatment of ADHD among adults, and possibly adolescents, with SUD can reduce their risk of relapse. Theoretical mechanisms that may explain the relationship between ADHD and SUD are explored in this paper. Current research and recommended clinical practices related to the diagnosis and treatment of ADHD with SUD in adolescents are discussed as well. More research is needed to definitively assess the effectiveness and safety of medications in this population of youths with ADHD and SUD.     

Differential genetic and environmental influences on developmental trajectories of antisocial behavior from adolescence to young adulthood

Little research has investigated differential genetic and environmental influences on different developmental trajectories of antisocial behavior. This study examined genetic and environmental influences on liabilities of being in life-course-persistent (LCP) and adolescent-limited (AL) type delinquent groups from adolescence to young adulthood while considering nonviolent and violent delinquency subtypes and gender differences. A genetically informative sample (n = 356, 15–16 years) from the first three waves of In-Home Interview of the National Longitudinal Study of Adolescent to Adult Health was used, with 94 monozygotic and 84 dizygotic pairs of same-sex twins (50% male). Biometric liability threshold models were fit and found that the male-specific LCP type class, chronic, showed more genetic influences, while the AL type classes, decliner and desister, showed more environmental influences. Genetic liability and shared environment both influence the persistence of antisocial behavior. The development of female antisocial behavior appears to be influenced more by shared environment.     

Unravelling the Link Between Prenatal Stress,Dopamine and Substance Use Disorder

Substance use disorder (SUD) refers to the detrimental use of psychoactive substances and it is related to a cluster of behavioural, cognitive and physiological dysfunctions indicating that the individual continues using the substance despite significant substance-related problems. Although it is one of the most prevalent neuropsychiatric diseases affecting society worldwide, the mechanism underlying the vulnerability of certain individuals is not well understood yet. It is now widely accepted that, in addition to genetic factors, environmental adversities during critical stages of development of an organism could also be considered as risk factors that contribute to SUD. It has been suggested that prenatal stress (PS) could play an important role in the causal mechanisms of SUD, since it was shown that PS leads individuals to poor stress management and behavioural problems, both of which increase the risk of SUD. It is widely accepted that gestational stress exposure in rats interferes with the correct progeny development. In particular, research in this field points out that the development of the mesocorticolimbic dopaminergic (DA) system is sensitive to disruption by exposure to early stressors. Interestingly, PS induces behavioural abnormalities that are similar to those observed in individuals that present SUD. Since dysfunction of mesocorticolimbic DA pathway has been reported in both prenatally stressed and SUD individuals, in this review we will summarise the current knowledge supporting that PS may serve as a strong candidate to explain the vulnerability of certain individuals to develop SUD following repeated drug exposure. We will also propose a mechanistic hypothesis to explain PS-induced changes on mesocorticolimbic DA system.