A recent genome wide association study reported evidence for association between rs1344706 within ZNF804A (encoding zinc finger protein 804A) and schizophrenia (P=1.61 ×10−7), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 ×10−9). Here we provide additional evidence for association through meta-analysis of a larger dataset (schizophrenia/schizoaffective disorder N = 18945, schizophrenia plus bipolar disorder N =21274, controls N =38675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high density LD mapping. Meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 ×10−11, OR=1.10, 95% CI 1.07–1.14) and schizophrenia and bipolar disorder combined (P=4.1 ×10−13, OR=1.11, 95% CI 1.07–1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
Major depression is the commonest psychiatric disorder and in the U.S. has the greatest impact of all biomedical diseases on disability. Here we review evidence of the genetic contribution to disease susceptibility and the current state of molecular approaches. Genome-wide association and linkage results provide constraints on the allele frequencies and effect sizes of susceptibility loci, which we use to interpret the voluminous candidate gene literature. We consider evidence for the genetic heterogeneity of the disorder and the likelihood that subtypes exist that represent more genetically homogenous conditions than have hitherto been analyzed.
Genetic analysis of major depression lags behind that of other disease. Genome-wide association and linkage results provide constraints on major depression’s genetic architecture, indicating that candidate gene studies are underpowered. The disorder is heterogeneous; subtypes likely exist that represent more homogenous conditions suitable for genetic dissection.
Rates of tobacco smoking are significantly higher in patients with schizophrenia compared with the general population. The underlying mechanism for this comorbidity is unclear. One hypothesis is that there are common genetic factors that predispose to both nicotine dependence (ND) and schizophrenia. To investigate this hypothesis, we examined the association of the 15q25 gene cluster, the most significant candidate region to date implicated in ND and smoking behavior, with schizophrenia and bipolar disorder.
Five variants in the 15q25 gene cluster (rs951266, rs16969968, rs1051730, rs8040868, and rs17477223) were selected to test for association with schizophrenia diagnosis, bipolar disorder diagnosis, and the presence of negative symptoms of schizophrenia. Effects of the variants on 15q25 gene expression were analyzed using publically available postmortem brain expression data.
A meta-analysis revealed four markers associated with risk for schizophrenia and bipolar disorder (rs951266, rs16969968, rs8040868, and rs17477223), and with the presence of negative symptoms of schizophrenia (rs951266, rs1051730, rs8040868, and rs17477223). The associations were in the same direction as that found for ND. Gene expression analysis indicated an association between genotypes of the rs1051730 variant and CHRNA5 expression in brain and peripheral blood mononuclear cells, and with the rs16969968 and rs17477223 variants in brain.
Variants in the 15q25 gene cluster are associated with risk for schizophrenia/bipolar illness, negative symptoms of schizophrenia, and influence CHRNA5 expression in the brain and peripheral blood mononuclear cells. These results are consistent with the notion that there are genetic mechanisms common to schizophrenia, ND, and bipolar disorder.
15q25 gene cluster; bipolar disorder; CHRNA5; nicotine dependence; schizophrenia
Epidemiologic research on traumatic stress is limited in Norway. Prevalence and correlates of exposure to potentially traumatic events (PTEs) and Posttraumatic stress disorder (PTSD), and patterns of comorbidity with DSM-IV Axis I and II disorders were examined in an epidemiologic sample.
Demographics, PTEs, and resulting PTSD, and comorbid DSM-IV diagnoses were assessed in 2,794 members of the Norwegian Institute of Public Health Twin Panel. The sample was 37% male, with an average age of 28.2 years (SD=3.9).
Approximately one-quarter of participants had lifetime PTE exposure; most PTEs were more common in men than in women. Lifetime prevalence of PTSD was 2.6%, and was significantly more common in women than men. Being female and type of PTE (both interpersonal and accidental traumatic events) were associated with increased PTSD symptoms, whereas higher education was associated with lower symptoms. PTSD was related to increased odds of most Axis I and II conditions.
PTE exposure and PTSD prevalence were lower than in the US, but comparable to other European countries. Sex differences replicated previous research. The relationship between PTSD and Borderline Personality Disorder was significantly stronger than the relationship between PTSD and any other Axis II conditions.
traumatic stress; posttraumatic stress disorder; comorbidity; Axis I; Axis II
A diagnosis of alcohol dependence (AD) using the DSM-IV-R is categorical, based on an individual’s manifestation of three or more symptoms from a list of seven. AD risk can be traced to both genetic and environmental sources. Most genetic studies of AD risk implicitly assume that an AD diagnosis represents a single underlying genetic factor. We recently found that the criteria for an AD diagnosis represent three somewhat distinct genetic paths to individual risk. Specifically, heavy use and tolerance versus withdrawal and continued use despite problems reflected separate genetic factors. However, some data suggest that genetic risk for AD is adequately described with a single underlying genetic risk factor. Rodent animal models for alcohol-related phenotypes typically target discrete aspects of the complex human AD diagnosis. Here, we review the literature derived from genetic animal models in an attempt to determine whether they support a single-factor or multiple-factor genetic structure. We conclude that there is modest support in the animal literature that alcohol tolerance and withdrawal reflect distinct genetic risk factors, in agreement with our human data. We suggest areas where more research could clarify this attempt to align the rodent and human data.
Withdrawal; Tolerance; Genetic correlations; Gene expression
Prior studies suggest that antisocial behavior in childhood and adolescence reflects multiple symptomatic dimensions. However, to our knowledge, no prior study has evaluated the underlying nature of the etiologic influences contributing to conduct disorder (CD) symptoms as defined in the DSM.
To determine the structure of genetic and environmental risk factors for CD.
Population-based twin registry.
Two thousand seven hundred sixty-nine members of male-male twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.
Main Outcome Measure
Retrospective self-reported symptoms of CD.
The best-fitting multivariate twin model included 2 genetic factors, 1 shared environmental common factor, and 1 nonshared environmental common factor, along with criterion-specific genetic and nonshared environmental effects. The CD criteria with the strongest loadings on the 2 genetic factors were, respectively, those reflecting rule breaking (eg, playing hooky) and overt aggressive acts (eg, hurting people). The shared environ mental common factor had salient loadings on a distinct set of criteria reflecting covert delinquent acts (eg, stealing and hurting animals). Loadings on the single non-shared environmental common factor were more uniform and less selective. Scores on the 3 familial CD factors were differentially associated with a range of personality, psychopathology, and demographic factors.
From a genetic perspective, the DSM criteria for CD do not reflect a single dimension of liability. The familial risk to CD is composed of 2 discrete dimensions of genetic risk, reflecting rule breaking and overt aggression, and 1 dimension of shared environmental risk, reflecting covert delinquency. These 3 familial factors differ meaningfully in their association with a range of relevant validators.
The nature of the relationship between major depression (MD) and phenotypes related to smoking behavior, including nicotine dependence (ND), is complicated. We present results from analyses comparing models wherein MD and ND are influenced by a shared latent factor to one in which causal pathways between phenotypes are examined.
Data were collected for 2906 adult male twins from a population-based sample. Structural equation modeling was used to derive path estimates for shared liability and causal models. MD was assessed according to DSM-III-R diagnostic criteria; ND was assessed using the Fagerstrom Test for Nicotine Dependence (FTND).
The best fitting shared liability model included genetic, but not environmental, influences shared between MD and FTND; a small proportion of these shared influences were also common to smoking initiation. The best fitting causal model included a unidirectional causal path from FTND to MD, with no direct genetic correlation between MD and smoking initiation. Model fit statistics indicated that these models provided nearly identical fits to the data, with the causal model providing a slightly superior AIC value.
The phenotypic association between MD and FTND is likely due to both a causal relationship, wherein increasing levels of nicotine dependence increase one’s risk for depression, and to a shared genetic liability between the two.
This sample consists of Caucasian males born in Virginia, and findings might not be generalizable to others. Statistical power was less than ideal.
nicotine dependence; major depression; shared liability; causal relationship
Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.
Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor.
No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/ disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples.
The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).
The direction of causation between measures of disrupted sleep, anxiety and depression is not well understood. Under certain conditions, cross sectional analysis based on genetically informative data can provide important information about the direction of causation between variables. Two community-based samples of 7,235 Australian twins aged 18 to 87 years were mailed an extensive questionnaire that covered a wide range of personality and behavioral measures. Included were self-report measures of disrupted sleep as well as symptoms of anxiety and depression. Among all females, modeling the direction of causation did not support the hypothesis of sleep having a direct causal impact on risk of anxiety or depression. Among older females, we found evidence that both anxiety and depression interact reciprocally with disrupted sleep whereas among younger women, both anxiety and depression appear to have a causal impact on sleep. Results for males were equivocal. The nosological implications of our findings are discussed.
Disrupted sleep; anxiety; depression; twins; genes; environment; direction of causation
Alcohol use disorders (AUDs) are clinically heterogeneous and strongly influenced by familial/genetic factors. Can we identify specific clinical features of AUDs that index familial liability to illness?
In twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders meeting DSM-IV criteria for lifetime AUDs, we examined whether clinical features of AUDs, including individual DSM-IV criteria for alcohol dependence (AD) and alcohol abuse (AA), predicted risk for AUDs in cotwins and/or parents. Analyses of individual criterion were repeated controlling for the total number of endorsed criteria.
Across these analyses, examining narrowly and broadly defined AUDs, risk of AUDs in relatives was more consistently predicted by abuse criteria than by dependence criteria, and by criteria reflecting negative psychosocial consequences rather than pharmacologic/biological criteria. Age at onset (AAO) poorly predicted risk in relatives. AUD associated legal problems, the one criterion slated for removal in DSM-5, was the most consistent single predictor of familial risk. Associations observed between individual criteria and risks of illness in relatives were generally stronger in monozygotic than dizygotic twin pairs, suggesting that these symptoms reflect a genetic risk for AUDs.
Individual DSM-IV criteria for AA and AD differ meaningfully in the degree to which they reflect the familial/genetic liability to AUDs. Contrary to expectation, the familial/genetic risk to AUDs was better reflected by symptoms of abuse and negative psychosocial consequences of AUD than by early AAO, or symptoms of tolerance and withdrawal.
Alcohol Abuse; Alcohol Dependence; Twin Studies; Heritability; Symptoms
Whereas the heritability of common personality traits has been firmly established, the results of the few published studies on personality disorders (PDs) are highly divergent, with some studies finding high heredity and others very low. A problem with assessing personality disorders by means of interview is errors connected with interviewer bias. A way to overcome the problem is to use self-report questionnaires in addition to interviews. This study used both interview and questionnaire for assessing DSM-IV Cluster B personality disorders: antisocial personality disorder (APD), borderline (BPD), narcissistic (NPD), and histrionic (HPD).
We assessed close to 2,800 twins from the Norwegian Institute of Public Health Twin Panel using a self-report questionnaire and, a few years later, the Structured Interview for DSM-IV Personality (SIDP-IV). Items from the self-report questionnaire that best predicted the PDs captured by the interview were then selected. Measurement models combining questionnaire and interview information were applied and were fitted using Mx.
Whereas the heritability of Cluster B PDs assessed by interview was around .30, and around .40–.50 when assessed by self-report questionnaire, the heritability of the convergent latent factor, including information from both interview and self-report questionnaire was .69 for APD, .67 for BPD, .71 for NPD, and .63 for HPD. As is usually found for personality, the effect of shared-in families (familial) environment was zero.
In conclusion, when both interview and self-report questionnaire are taken into account, the heritability of Cluster B PD appears to be in the upper range of previous findings for mental disorders.
An early age at menarche is associated with disordered eating in women. However, it is unclear whether they share genetic factors. The goal of the current study is to delineate the genetic correlation between age at menarche and disordered eating.
Participants included 427 monozygotic and 329 dizygotic 16-17 year-old female twins from the Swedish Twin Study of Child and Adolescent Development. Disordered eating was assessed with the Eating Disorder Inventory-2. Age at menarche was assessed via self-report. A bivariate correlated factors model was used to delineate the genetic correlation between age at menarche and disordered eating.
The analysis revealed a negative genetic correlation of −.18 in the best-fit model indicating that the genetic factors that influence younger age at menarche are associated with increased liability for disordered eating.
Future research should examine possible causes for this correlation such as the estrogen system and gene-environment interactions.
disordered eating; puberty; adolescence; twin study
Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
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.