We fitted ordinal latent growth models to measures of drug availability to determine the trajectories of genetic and environmental effects over time.
This report is based on data collected from 1789 adult males from the Mid Atlantic Twin Registry who participated in a structured telephone interview which included five retrospective assessments of drug availability between ages 8 and 25. Biometric univariate analysis revealed significant familial aggregation for all five measures of drug availability. In order to model latent growth, interval information (means and variance) was extracted from the ordinal data by simultaneously fitting a threshold invariant and multivariate Dual Change Score models. This permits the estimation of latent genetic and environmental trajectories over time.
The relative proportions of genetic and environmental effects appear to be time dependent. There was a general increase in additive genetic and decrease in shared environmental effects over time. Stimulants were the only exception.
The upswing in genetic and specific environmental effects might be the result of acceleration in the expression of individual differences, and reductions in the total number of social constraints which may combine to make drugs easier to obtain.
drug availability; gene; environment; twin; longitudinal; growth; ordinal
Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, PSR and POR, were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant PSRP-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.
anxiety; neuroticism; panic disorder; linkage; meta-analysis
Recent evidence from empirical studies indicates that individuals who begin drinking at an early age may be more likely to use alcohol to cope with negative mood states and stress; however, the mechanisms underlying this association are unclear. One possibility is that early drinking directly increases risk for drinking to cope (DTC). Alternatively, the association between early drinking and DTC may be indirect, attributable to overlapping genetic or environmental factors. No prior genetically informative study has investigated the sources of covariation underlying the early-onset drinking-DTC association.
Early-onset drinking (before age 15) was assessed using structured clinical interviews in a sample of 7130 male and female participants aged 19–56 years from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD, Kendler & Prescott, 2006). DTC was assessed using the mood management scale of the alcohol use inventory (Horn & Wanberg, 1983). The sources of the covariation between early first drink and DTC were estimated using bivariate twin modeling.
Early drinking onset was reported by 28% of males and 16% of females and was associated with significantly higher DTC scores (phenotypic correlation: males = .19, females = .22). Results from bivariate twin models indicated that the association between early-onset drinking and DTC was completely attributable to shared genetic factors that contribute to both behaviors.
Greater DTC among early-onset drinkers may not reflect a direct causal process, as shared biological pathways may explain vulnerability to stress-related drinking seen among early-onset drinkers.
Drinking motives; Alcohol; Early-onset drinking; Twin; Genetic
It is unclear whether direct structured interviews are able to capture the full range of psychopathology in schizophrenia, as is required in diagnostic assessments or clinical ratings. We examined agreement between symptom ratings derived from direct patient interviews and from review of casenotes.
The study sample comprised 1021 schizophrenic subjects collected as part of the Irish Case-Control Study of Schizophrenia (ICCSS). Diagnostic interviews utilized a modified version of the Structured Clinical Interview for DSM-III-R. Symptoms were rated by the interviewer. In addition, the Casenote Rating Scale was used to rate symptoms based on medical record information. For each negative and positive symptom, we calculated the Pearson correlation between the interview and the casenote rating. Using the mean of the interview and casenote rating for each symptom, exploratory factor analysis using Varimax rotation was performed.
Three factors were extracted in factor analysis: positive, negative, and Schneiderian symptoms. The highest correlations between interview and casenote ratings were for negative symptoms, in which all symptoms were significantly correlated. Positive and Schneiderian symptoms were significantly correlated with the exception of thought insertion, thought withdrawal, voices speaking in sentences, and somatic hallucinations. Significant correlations were generally moderate (0.2–0.55)
Most schizophrenic symptoms, especially negative symptoms, can be assessed by direct interviews as the sole source of information with moderate reliability. However, the presence of some Schneiderian and possibly less prevalent positive symptoms may be difficult to determine without a review of records, which may include longitudinal observations and information from multiple observers.
schizophrenia; clinical features; structured interview; factor analysis
Large genomic copy number variations (CNVs) have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.
To detect novel CNVs increasing susceptibility to schizophrenia, utilizing two ethnically homogeneous discovery cohorts and replication in large samples.
Genetic association study of microarray data.
DNA samples were collected at nine sites from different countries.
Two discovery cohorts were comprised of: a) 790 cases (schizophrenia and schizoaffective disorder) and 1347 controls of Ashkenazi Jewish descent; and b) 662 trios (offspring affected with schizophrenia or schizoaffective disorder) from Bulgaria. Replication datasets consisted of 12,398 cases and 17,945 controls.
Main outcome measure
Statistically increased rate of specific CNVs in cases versus controls.
One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 out of 13,850 cases (0.094%) and in 3 out of 19,954 controls (0.015%), Fisher Exact p = 0.0014; OR = 6.25 (95%CI = 1.78 – 21.93).
Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains nine genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional eight genes. Our findings add a new locus to the list of CNVs that increase risk to develop schizophrenia.
Twin studies suggest that Conduct Disorder (CD) is under substantial genetic influence, which is stronger for aggressive than for non-aggressive symptoms. Studies of migrating populations offer an alternative strategy for separating environmental and genetic influences on psychopathology.
To examine variation in the prevalence of CD associated with migration from Mexico to the US and whether this variation is similar for aggressive and non-aggressive CD symptoms and symptom profiles.
The prevalence of CD, different types of CD symptoms and CD symptom profiles were compared across three generations of people of Mexican origin with increasing levels of exposure to American culture: families of origin of migrants (in Mexico), children of Mexican migrants raised in the US and Mexican-American children of US-born parents.
General population surveys conducted in Mexico and the US using the same diagnostic interview.
Adults age 18–44 in the household population of Mexico and the household population of people of Mexican descent in the US.
Main Outcome Measures
CD criteria assessed using the World Mental Health version of the Composite International Diagnostic Instrument (WMH-CIDI).
Compared with families of origin of migrants, risk of CD is lower in the general population of Mexico (OR=0.54, 95% CI 0.19–1.51), higher in children of Mexican-born immigrants who are raised in the US (OR=4.12, 95% CI 1.47–11.52) and higher still in Mexican-American children of US-born parents (OR=7.64, 95% CI 3.20–18.27). The association with migration is markedly weaker for aggressive than for non-aggressive symptoms.
The prevalence of CD increases dramatically across generations of the Mexican-origin population following migration to the US. This increase is of larger magnitude for non-aggressive than for aggressive symptoms, consistent with the suggestion that non-aggressive symptoms are more strongly influenced by environmental factors than aggressive symptoms.
Previous studies examined caffeine use and caffeine dependence and risk for the symptoms, or diagnosis, of psychiatric disorders. The current study aimed to determine if generalized anxiety disorder (GAD), panic disorder, phobias, major depressive disorder (MDD), anorexia nervosa (AN), or bulimia nervosa (BN) shared common genetic or environmental factors with caffeine use, caffeine tolerance, or caffeine withdrawal.
Using 2,270 women from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, bivariate Cholesky decomposition models were used to determine if any of the psychiatric disorders shared genetic or environmental factors with caffeine use phenotypes.
GAD, phobias, and MDD shared genetic factors with caffeine use, with genetic correlations estimated to be 0.48, 0.25, and 0.38, respectively. Removal of the shared genetic and environmental parameter for phobias and caffeine use resulted in a significantly worse fitting model. MDD shared unique environmental factors (environmental correlation = 0.23) with caffeine tolerance; the genetic correlation between AN and caffeine tolerance and BN and caffeine tolerance were 0.64 and 0.49, respectively. Removal of the genetic and environmental correlation parameters resulted in significantly worse fitting models for GAD, phobias, MDD, AN, and BN, which suggested that there was significant shared liability between each of these phenotypes and caffeine tolerance. GAD had modest genetic correlations with caffeine tolerance, 0.24, and caffeine withdrawal, 0.35.
There was suggestive evidence of shared genetic and environmental liability between psychiatric disorders and caffeine phenotypes. This might inform us about the etiology of the comorbidity between these phenotypes.
anxiety disorders; depression; eating disorders; caffeine; heritability
Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted.
We investigated measurement non-invariance of DSM-IV narcissistic personality disorder (NPD) criteria across age and sex in a population-based cohort sample of 2794 Norwegian twins. Age had a statistically significant effect on the factor mean for NPD. Sex had a statistically significant effect on the factor mean and variance. Controlling for these factor level effects, item-level analysis indicated that the criteria were functioning differently across age and sex. After correcting for measurement differences at the item level, the latent factor mean effect for age was no longer statistically significant. The mean difference for sex remained statistically significant after correcting for item threshold effects. The results indicate that DSM-IV NPD criteria perform differently in males and females and across age. Differences in diagnostic rates across groups may not be valid without correcting for measurement non-invariance.
narcissistic personality disorder; twins; population-based sample; item response theory; measurement non-variance
Posttraumatic stress disorder (PTSD) is one of the only DSM disorders that require an environmental exposure. The relationship between liability factors for trauma exposure and those for PTSD symptoms following exposure are unclear.
Exposure to a trauma and resulting PTSD symptoms were assessed in a sample of 2,794 members of the Norwegian Institute of Public Health Twin Panel.
In the full sample, 737 twins experienced a trauma. A modified causal, contingent, common pathway (CCC) model was used to examine trauma exposure and liability for PTSD. Genetic and common environmental factors could not be distinguished, so a model that included only familial and individual specific components was fit. The best-fitting model suggested that familial factors played an important role in liability for trauma exposure and for resulting PTSD symptoms, and that there was a modest transmission between trauma exposure and subsequent PTSD symptoms.
One third of the variance in liability of PTSD symptoms is due to familial factors, and of this, approximately one-fifth overlaps with the familial liability for trauma exposure while the other four-fifths of the variance is specific to the risk of PTSD symptoms following exposure. The hypothesis that PTSD is etiologically similar to exposures to a traumatic event is not supported, suggesting that the factors that confer risk for trauma do not overlap completely with those that confer risk for PTSD.
twins; posttraumatic stress disorder; epidemiology
Our aim was to profile alcohol and cannabis initiation and to characterize the effects of developmental and environmental risk factors on changes in average drug use over time.
We fitted a two-part random effects growth model to identify developmental and environmental risks associated with alcohol and cannabis initiation, initial average use and changes in average use.
1796 males aged 24–63 from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.
Data from three interview waves included self-report measures of average alcohol and cannabis use between ages 15 and 24, genetic risk of problem drug use, childhood environmental risks, personality, psychiatric symptoms, as well as personal, family and social risk factors.
Average alcohol and cannabis use were correlated at all ages. Genetic risk of drug use based on family history, higher sensation seeking, and peer group deviance predicted both alcohol and cannabis initiation. Higher drug availability predicted cannabis initiation while less parental monitoring and drug availability were the best predictors of how much cannabis individuals consumed over time.
The liability to initiate alcohol and cannabis, average drug use as well as changes in drug use during teenage years and young adulthood is associated with known risk factors.
Alcohol; Cannabis; Initiation; Longitudinal; Risks; Two-part random effects; Latent class; Growth curve; Mixture distributions
One of the main controversies with regard to depressive personality disorder (DPD) concerns the co-occurrence with the established DSM-IV personality disorders (PDs). The main aim of this study was to examine to what extent DPD and the DSM-IV PDs share genetic and environmental risk factors, using multivariate twin modeling. The DSM-IV Structured Interview for Personality was applied to 2,794 young adult twins. Paranoid PD from Cluster A, borderline PD from Cluster B, and all three PDs from Cluster C were independently and significantly associated with DPD in multiple regression analysis. The genetic correlations between DPD and the other PDs were strong (.53–.83), while the environmental correlations were moderate (.36–.40). Close to 50% of the total variance in DPD was disorder specific. However, only 5% was due to disorder-specific genetic factors, indicating that a substantial part of the genetic vulnerability to DPD also increases the vulnerability to other PDs.
The current study examined the association between substance use in the household during childhood, parental attitudes towards substance use and lifetime substance use in males. Subjects included 1081 monozygotic and 707 dizygotic twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Retrospective reports of substance use and features of the family environment (adult household substance use and parental attitudes towards substance use) were obtained using a life history interview. A trivariate Cholesky decomposition was conducted using the program Mx to decompose common shared environmental variance. Findings suggest that family environmental factors accounted for a large proportion of the shared environmental effects for illicit drug use. Results illustrate an important way of extending behavior genetic research to reveal specific etiological environmental mechanisms.
Substance use; Shared environment; Family environment; Twins; Twin study
Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the “missing heritability” of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q–Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders.
Genome-wide association studies (GWAS) have thus far identified only a small fraction of the heritability of common complex disorders, such as severe mental disorders. We used a conditional false discovery rate approach for analysis of GWAS data, exploiting “genetic pleiotropy” to increase discovery of common gene variants associated with schizophrenia and bipolar disorders. Leveraging the increased power from combining GWAS of two associated phenotypes, we found a striking overlap in polygenic signals, allowing for the discovery of several new common gene variants associated with bipolar disorder and schizophrenia that were not identified in the original analysis using traditional GWAS methods. Some of the gene variants have been identified in other studies with large targeted replication samples, validating the present findings. Our pleiotropy-informed method may be of significant importance for detecting effects that are below the traditional genome-wide significance level in GWAS, particularly in highly polygenic, complex phenotypes, such as schizophrenia and bipolar disorder, where most of the genetic signal is missing (i.e., “missing heritability”). The findings also offer insights into mechanistic relationships between bipolar disorder and schizophrenia pathogenesis.
A study by Dawson and colleagues (Alcohol Clin Exp Res 2007; 31:69) using data from National Epidemiologic Survey on Alcohol and Related Condition found earlier drinking onset age, and higher levels of past-year stressful life events (SLE) were associated with higher past-year alcohol consumption. The aims of our study were as follows: (i) to attempt to replicate this interaction; (ii) to extend it by examining sex and event dependence as potential moderators of the effect; and (iii) to estimate the roles of genetic and environmental factors in mediating the overlap of early drinking onset and SLE in their relations with alcohol consumption.
Data were from 1,382 female and 2,218 male drinkers interviewed as part of the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Regression models were used to evaluate the main and interactive effects of early drinking onset and moderate or severe past-year SLE on past-year drinking density (PYDD), a weighted quantity-frequency measure of alcohol consumption. Analyses adjusted for demographic covariates and were stratified by sex and whether SLE were independent or dependent on the person’s actions, as rated by interviewers. Structural twin models were used to estimate the degree to which early drinking onset, SLE, and their interaction accounted for additive genetic, common environmental and individual-specific variance in PYDD.
We replicated the prior finding of a main effect of higher alcohol consumption among individuals reporting earlier drinking onset. Age at drinking onset accounted for about 5% of the variation in PYDD, and this association was mostly attributable to overlapping genetic influences. Evidence for an interaction between onset age and SLE was generally weak, possibly because of lower power and other methodological differences from Dawson and colleagues’ study. However, there was some evidence consistent with an interaction of higher PYDD among early drinking men who experienced independent SLE and early drinking women with dependent SLE.
We confirmed prior findings of an association between early age at drinking onset with higher past-year drinking among young- and middle-aged adults and found limited evidence supporting a replication for higher stress-related drinking among early-onset drinkers. The association is consistent with early onset and stress-related drinking being attributable to overlapping genetic liability. Among early drinkers, our results suggest sex differences in consumption with regard to event dependence.
Age at First Drink; Stressful Life Events; Early-Onset Drinking; Twins; Sex Differences
Drug abuse (DA) strongly runs in families. Does this result solely from genetic factors or does the family environment contribute?
To determine the familial environmental contribution to the risk for DA.
Follow-up in 9 public databases (1961–2009) in siblings and spouses.
A total of 137 199 sibling pairs and 7561 spousal pairs containing a proband with DA and matched control probands.
Main Outcome Measures
Drug abuse recorded in medical, legal, or pharmacy registry records.
In the best-fit model, which contained significant linear, quadratic, and cubic effects, among full sibling pairs containing a proband with DA, the relative risk for DA in the sibling declined from more than 6.0 for siblings born within 2 years of each other to less than 4.5 when born 10 years apart. Controlling for age differences in full sibling pairs, the hazard rate for DA in a sibling when the affected proband was older vs younger was 1.42 (95% CI, 1.31–1.54). In the best-fit model, which contained significant linear, quadratic, and cubic effects, among spousal pairs containing a proband with DA, the relative risk for DA in the spouse declined from more than 25.0 within 1 year of proband DA registration to 6.0 after 5 years.
Controlling for genetic effects by examining only full siblings, sibling resemblance for the risk for DA was significantly greater in pairs closer vs more distant in age. Older siblings more strongly transmitted the risk for DA to their younger siblings than vice versa. After one spouse is registered for DA, the other spouse has a large short-lived increase in DA risk. These results support strong familial environmental influences on DA at various life stages. A complete understanding of the familial transmission of DA will require knowledge of how genetic and familial environmental risk factors act and interact over development.
This article describes three types of gene–environment interactions and the challenges inherent in interpreting these interactions. It also reports on what is known about gene–environment interactions in the field of alcohol use disorders (AUDs). Twin studies of the interaction of genetic and environmental influences on AUDs have resulted in relatively consistent findings and have suggested general mechanisms for interaction effects. These studies generally find that environments that exert more social control (e.g., higher parental monitoring, less migratory neighborhoods, etc.) tend to reduce genetic influences, whereas other environments allow greater opportunity to express genetic predispositions, such as those characterized by more deviant peers and greater alcohol availability. Conversely, the gene–environment literature that has been developed surrounding specific genes has focused largely on the role of stress as a moderator of genetic effects.
Alcohol use disorders (AUDs); genetic factors; environmental factors; genetic and environment interactions; twin studies; statistical models; stress; literature review
Generalized anxiety disorder (GAD) is a common, chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically-informative research has examined the potential sources of reported brain differences.
We acquired spectroscopic, volumetric, and diffusion tensor magnetic resonance imaging data from a pilot study of 34 female subjects selected from monozygotic twin pairs based upon their affection status for GAD and examined brain regions previously implicated in fear and anxiety for their relationship with affection status and genetic risk.
Lifetime GAD associated with increased creatine levels in the amygdala, smaller left hippocampal volume, and lower fractional anisotropy in the uncinate fasciculus which connects amygdala and frontal cortex. In addition, GAD genetic risk predicted increases in myo-inositol in the amygdala and, possibly, glutamate/glutamine/GABA alterations in the hippocampus. The association of lifetime GAD with smaller hippocampal volume was independent of major depression and might represent a common genetic risk marker for internalizing disorders.
These preliminary data suggest that GAD and its genetic risk factors are likely correlated with volumetric and spectroscopic changes in fear-related limbic structures and their connections with the frontal cortex.
Anxiety Disorders; Depressive Disorder; Twin Study; Magnetic Resonance Spectroscopy; Diffusion Tensor Imaging
To examine the negative statistical relationship between educational level and risk of anxiety disorders, and to estimate to what extent this relationship may be explained by genes or environmental factors influencing both phenotypes.
Registry data on educational level for 3339 young adult Norwegian twin pairs and diagnostic data on anxiety disorders for 1385 of these pairs were analyzed, specifying structural equations models using MX software.
In the best-fitting model genes accounted for 59% of the variance in education. 18% of the variance was due to environmental factors shared by co-twins, and the remaining 23% to nonshared environment. 46% of the variance in liability to anxiety disorders was genetic, the remaining variance was due to nonshared environment. A phenotypic polychoric correlation of −0.30 between educational level and ‘any anxiety disorder’ was estimated to be primarily (83% in the best-fitting model) caused by genes common to the two traits.
The relationship between low education and risk of anxiety disorders appears to be primarily determined by genetic effect common to educational level and anxiety disorders.
anxiety disorders; education; twins; population genetics
We introduce a method for detecting variants in several genes of related function with small effect on a phenotype of interest. Our method uses logistic regression to test whether multiple alleles within a functional set have significantly higher than expected predictive value, even though none individually may have strong individual effects. We illustrate this method by testing seven gene sets (including 48 genes), from a study with1350 single nucleotide polymorphisms in 130 addiction candidate genes studied in a sample of 575 alcohol dependence (AD) cases and 530 controls. We conclude that AD is related to variation in genes participating in Glutamate and GABA signaling, as has been reported elsewhere, and in stress response pathways, but not with genes in several other systems implicated in other drugs of abuse.
alcohol dependence; GABA; glutamate; CRH; logistic regression; neurotransmitter system
This article reviews current advances in the genetics of substance use disorders (SUDs). Both genetic and environmental sources of risk are required to develop a complete picture of SUD etiology. Genetic sources of risk for SUDs are not highly substance specific in their effects. Genetic and environmental risks for SUDs typically do not only add together but also interact with each other over development. Risk gene identification for SUDs has been difficult, with one recent success in identifying nicotinic receptor variants that affect risk for nicotine dependence. The impact of genetic variants on SUD risk will individually be small. Although genetic epidemiologic methods are giving us an increasingly accurate map of broad causal pathways to SUDs, gene discovery will be needed to identify the specific biological systems. Identifying these risk genes and understanding their action will require large clinical samples, and interaction between these studies and work in model organisms.
Many assessment instruments for psychopathy are multidimensional, suggesting that distinguishable factors are needed to effectively capture variation in this personality domain. However, no prior study has examined the factor structure of the DSM-IV criteria for antisocial personality disorder (ASPD).
Self-report questionnaire items reflecting all A criteria for DSM-IV ASPD were available from 4,291 twins (including both members of 1,647 pairs) from the Virginia Adult Study of Psychiatric and Substance Use Disorders. Exploratory factor analysis and twin model fitting were performed using, respectively, Mplus and Mx.
Phenotypic factor analysis produced evidence for 2 correlated factors: aggressive-disregard and disinhibition. The best-fitting multivariate twin model included two genetic and one unique environmental common factor, along with criteria-specific genetic and environmental effects. The two genetic factors closely resembled the phenotypic factors and varied in their prediction of a range of relevant criterion variables. Scores on the genetic aggressive-disregard factor score were more strongly associated with risk for conduct disorder, early and heavy alcohol use, and low educational status, whereas scores on the genetic disinhibition factor score were more strongly associated with younger age, novelty seeking, and major depression.
From a genetic perspective, the DSM-IV criteria for ASPD do not reflect a single dimension of liability but rather are influenced by two dimensions of genetic risk reflecting aggressive-disregard and disinhibition. The phenotypic structure of the ASPD criteria results largely from genetic and not from environmental influences.
antisocial personality disorder; psychopathy; genetics; twin study; diagnosis; environment
Childhood sexual abuse (CSA) is a traumatic life event associated with an increased lifetime risk for psychopathology/morbidity. The long-term biological consequences of CSA-elicited stress on chromosomal stability in adults are unknown. The primary aim of this study was to determine if the rate of acquired chromosomal changes, measured using the cytokinesis-block micronucleus assay on stimulated peripheral blood lymphocytes, differs in adult female monozygotic twins discordant for CSA.
Monozygotic twin pairs discordant for CSA were identified from a larger population-based sample of female adult twins for whom the experience of CSA was assessed by self-report (51 individuals including a reference sample). Micronuclei (MN) contain chromatin from structurally normal or abnormal chromosomes that are excluded from the daughter nuclei during cell division and serve as a biomarker to assess acquired chromosomal instability.
Female twins exposed to CSA exhibited a 1.63-fold average increase in their frequency of MN compared to their nonexposed genetically identical cotwins (Paired t-test, t16 = 2.65, P = 0.017). No additional effects of familial factors were detected after controlling for the effect of CSA exposure. A significant interaction between CSA history and age was observed, suggesting that the biological effects of CSA on MN formation may be cumulative.
These data support a direct link between CSA exposure and MN formation measured in adults that is not attributable to genetic or environmental factors shared by siblings. Further research is warranted to understand the biological basis for the observed increase in acquired chromosomal findings in people exposed to CSA and to determine if acquired somatic chromosomal abnormalities/somatic clonal mosaicism might mediate the adult pathology associated with CSA.
Prior research suggests that drug abuse (DA) is strongly influenced by both genetic and familial environmental factors. No large-scale adoption study has previously attempted to verify and integrate these findings.
To determine how genetic and environmental factors contribute to the risk for DA.
Follow-up in 9 public databases (1961–2009) of adopted children and their biological and adoptive relatives.
The study included 18 115 adopted children born between 1950 and 1993; 78 079 biological parents and siblings; and 51 208 adoptive parents and siblings.
Main Outcome Measures
Drug abuse recorded in medical, legal, or pharmacy registry records.
Risk for DA was significantly elevated in the adopted offspring of biological parents with DA (odds ratio, 2.09; 95% CI, 1.66–2.62), in biological full and half siblings of adopted children with DA (odds ratio, 1.84; 95% CI, 1.28–2.64; and odds ratio, 1.41; 95% CI, 1.19–1.67, respectively), and in adoptive siblings of adopted children with DA (odds ratio, 1.95; 95% CI, 1.43–2.65). A genetic risk index (including biological parental or sibling history of DA, criminal activity, and psychiatric or alcohol problems) and an environmental risk index (including adoptive parental history of divorce, death, criminal activity, and alcohol problems, as well as an adoptive sibling history of DA and psychiatric or alcohol problems) both strongly predicted the risk for DA. Including both indices along with sex and age at adoption in a predictive model revealed a significant positive interaction between the genetic and environmental risk indices.
Drug abuse is an etiologically complex syndrome strongly influenced by a diverse set of genetic risk factors reflecting a specific liability to DA, by a vulnerability to other externalizing disorders, and by a range of environmental factors reflecting marital instability, as well as psychopathology and criminal behavior in the adoptive home. Adverse environmental effects on DA are more pathogenic in individuals with high levels of genetic risk. These results should be interpreted in the context of limitations of the diagnosis of DA from registries.