Virginia Institute for Psychiatric and Behavioral Genetics

Richmond, VA, United States

Virginia Institute for Psychiatric and Behavioral Genetics

Richmond, VA, United States
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Eaves L.,Virginia Institute for Psychiatric and Behavioral Genetics
Twin Research and Human Genetics | Year: 2017

Background: There continues to be significant investment in the detection of genotype × environment interaction (G × E) in psychiatric genetics. The implications of the method of assessment for the genetic analysis of psychiatric disorders are examined for simulated twin data on symptom scores and environmental covariates. Methods: Additive and independent genetic and environmental risks were simulated for 10,000 monozygotic (MZ) and 10,000 dizygotic (DZ) twin pairs and the ‘subjects’ administered typical simulated checklists of clinical symptoms and environmental factors. A variety of standard tests for G × E were applied to the simulated additive risk scores, sum scores derived from the checklists and transformed sum scores. Results: All analyses revealed no evidence for G × E for latent risk but marked evidence for G × E and other effects of modulation in the sum scores. These effects were all removed by transformation. An integrated genetic and psychometric model, accounting for both the causes of latent liability and a theory of measurement, was fitted to a sample of the simulated sum-score data and showed that there was no significant modulation of the parameters of the genetic model by environmental covariates (i.e., no G × E). Conclusions: Claims to detect G × E based on analytical methods that ignore the theory of measurement must be subjected to greater scrutiny prior to publication. Copyright © The Author(s) 2017


Aberg K.,Center for Biomarker Research and Personalized Medicine | Adkins D.E.,Center for Biomarker Research and Personalized Medicine | Bukszar J.,Center for Biomarker Research and Personalized Medicine | Webb B.T.,Center for Biomarker Research and Personalized Medicine | And 12 more authors.
Biological Psychiatry | Year: 2010

Background: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. Methods: We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia. Results: Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 × 10-10 and p = 3.8 × 10-7, respectively, and one for AIMS, rs7669317 with p = 7.7 × 10-8, reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. Conclusions: Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics. © 2010 Society of Biological Psychiatry.


Chou L.-N.,National Taiwan University | Kuo P.-H.,National Cheng Kung University | Kuo P.-H.,Virginia Institute for Psychiatric and Behavioral Genetics | Lin C.C.H.,Eli Lilly and Company | And 3 more authors.
Behavior Genetics | Year: 2010

This study aimed to estimate the relative contributions from genetic and environmental factors to the Wisconsin Card Sorting Test (WCST) performance, a widely used measurement for assessing frontal lobe function. Participants included 350 pairs of twins (257 MZ and 93 DZ) and 47 same-sex sib-pairs, aged 12-16 years, systematically recruited from junior high schools in Taipei. A computerized version of the WCST was administered for each participant and its nine indexes were used for subsequent analysis. Univariate analysis in structural equation modeling was performed for each WCST index using Mx program. The ACE model for each WCST index indicated no significant genetic influence, whereas the shared environmental influence ranged from 30 to 38% for four indexes (Perseverative Errors, Perseverative Responses, Categories Achieved, and Conceptual Level Responses). We concluded that WCST performance might be an indicator more for environmental insult than for genetic influences on frontal lobe function. © 2009 Springer Science+Business Media, LLC.


Agrawal A.,University of Washington | Silberg J.L.,Virginia Institute for Psychiatric and Behavioral Genetics | Lynskey M.T.,University of Washington | Maes H.H.,Virginia Institute for Psychiatric and Behavioral Genetics | Eaves L.J.,Virginia Institute for Psychiatric and Behavioral Genetics
Drug and Alcohol Dependence | Year: 2010

Using twins assessed during adolescence (Virginia Twin Study of Adolescent Behavioral Development: 8-17 years) and followed up in early adulthood (Young Adult Follow-Up, 18-27 years), we tested 13 genetically informative models of co-occurrence, adapted for the inclusion of covariates. Models were fit, in Mx, to data at both assessments allowing for a comparison of the mechanisms that underlie the lifetime co-occurrence of cannabis and tobacco use in adolescence and early adulthood. Both cannabis and tobacco use were influenced by additive genetic (38-81%) and non-shared environmental factors with the possible role of non-shared environment in the adolescent assessment only. Causation models, where liability to use cannabis exerted a causal influence on the liability to use tobacco fit the adolescent data best, while the reverse causation model (tobacco causes cannabis) fit the early adult data best. Both causation models (cannabis to tobacco and tobacco to cannabis) and the correlated liabilities model fit data from the adolescent and young adult assessments well. Genetic correlations (0.59-0.74) were moderate. Therefore, the relationship between cannabis and tobacco use is fairly similar during adolescence and early adulthood with reciprocal influences across the two psychoactive substances. However, our study could not exclude the possibility that 'gateways' and 'reverse gateways', particularly within a genetic context, exist, such that predisposition to using one substance (cannabis or tobacco) modifies predisposition to using the other. Given the high addictive potential of nicotine and the ubiquitous nature of cannabis use, this is a public health concern worthy of considerable attention. © 2009 Elsevier Ireland Ltd. All rights reserved.


Janak P.H.,University of California at San Francisco | Bowers M.S.,Virginia Institute for Psychiatric and Behavioral Genetics | Corbit L.H.,University of California at San Francisco | Corbit L.H.,University of Sydney
Neuropsychopharmacology | Year: 2012

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; OBrien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies. © 2012 American College of Neuropsychopharmacology. All rights reserved.


Cramer A.O.J.,University of Amsterdam | Borsboom D.,University of Amsterdam | Aggen S.H.,Virginia Institute for Psychiatric and Behavioral Genetics | Aggen S.H.,Virginia Commonwealth University | And 2 more authors.
Psychological Medicine | Year: 2012

Background Previous research has shown that stressful life events (SLEs) influence the pattern of individual depressive symptoms. However, we do not know how these differences arise. Two theories about the nature of psychiatric disorders have different predictions about the source of these differences: (1) SLEs influence depressive symptoms and correlations between them indirectly, via an underlying acute liability to develop a dysphoric episode (DE; common cause hypothesis); and (2) SLEs influence depressive symptoms and correlations between them directly (network hypothesis). The present study investigates the predictions of these two theories.Method We divided a population-based sample of 2096 Caucasian twins (49.9% female) who reported at least two aggregated depressive symptoms in the last year into four groups, based on the SLE they reported causing their symptoms. For these groups, we calculated tetrachoric correlations between the 14 disaggregated depressive symptoms and, subsequently, tested whether the resulting correlation patterns were significantly different and if those differences could be explained by underlying differences in a single acute liability to develop a DE.Results The four SLE groups had markedly different correlation patterns between the depressive symptoms. These differences were significant and could not be explained by underlying differences in the acute liability to develop a DE.Conclusions Our results are not compatible with the common cause perspective but are consistent with the predictions of the network hypothesis. We elaborate on the implications of a conceptual shift to the network perspective for our diagnostic and philosophical approach to the concept of what constitutes a psychiatric disorder. © Cambridge University Press 2011.


Bowers M.S.,Virginia Institute for Psychiatric and Behavioral Genetics | Bowers M.S.,Institute for Drug and Alcohol Studies | Chen B.T.,University of California at San Francisco | Bonci A.,University of California at San Francisco | Bonci A.,Wheeler Center for the Neurobiology of Addiction
Neuron | Year: 2010

Experience-dependent plasticity at excitatory synapses of the mesocorticolimbic system is a fundamental brain mechanism that enables adaptation to an ever-changing environment. These synaptic responses are critical for the planning and execution of adaptive behaviors that maximize survival. The mesocorticolimbic system mediates procurement of positive reinforcers such as food and sex; however, drugs of abuse resculpt this crucial circuitry to promote compulsive drug-seeking behavior. This review will discuss the long-term changes in glutamatergic neurotransmission that occur within the mesolimbic system following cocaine exposure. In addition, we will examine how these long-lasting neuroadaptations may drive the pathology of psychostimulant addiction. Finally, we review clinical trials that highlight antagonists at excitatory AMPA receptors as promising targets against cocaine abuse. © 2010 Elsevier Inc.


Barclay N.L.,Northumbria University | Gehrman P.R.,University of Pennsylvania | Gregory A.M.,Goldsmiths, University of London | Eaves L.J.,Virginia Institute for Psychiatric and Behavioral Genetics | Silberg J.L.,Virginia Commonwealth University
Sleep | Year: 2015

Study Objectives: To determine prevalence and heritability of insomnia during middle/late childhood and adolescence; examine longitudinal associations in insomnia over time; and assess the extent to which genetic and environmental factors on insomnia remain stable, or whether new factors come into play, across this developmental period.Design: Longitudinal twin study.Setting: Academic medical center.Patients or Participants: There were 739 complete monozygotic twin pairs (52%) and 672 complete dizygotic twin pairs (48%) initially enrolled and were followed up at three additional time points (waves). Mode ages at each wave were 8, 10, 14, and 15 y (ages ranged from 8-18 y).Interventions: None.Measurements and Results: Clinical ratings of insomnia symptoms were assessed using the Child and Adolescent Psychiatric Assessment (CAPA) by trained clinicians, and rated according to Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition-Revised criteria for presence of "clinically significant insomnia," over four sequential waves. Insomnia symptoms were prevalent but significantly decreased across the four waves (ranging from 16.6% to 31.2%). "Clinically significant insomnia" was moderately heritable at all waves (h2 range = 14% to 38%), and the remaining source of variance was the nonshared environment. Multivariate models indicated that genetic influences at wave 1 contributed to insomnia at all subsequent waves, and that new genetic influences came into play at wave 2, which further contributed to stability of symptoms. Nonshared environmental influences were time-specific.Conclusion: Insomnia is prevalent in childhood and adolescence, and is moderately heritable. The progression of insomnia across this developmental time period is influenced by stable as well as new genetic factors that come into play at wave 2 (modal age 10 y). Molecular genetic studies should now identify genes related to insomnia progression during childhood and adolescence.


Ystrom E.,Norwegian Institute of Public Health | Reichborn-Kjennerud T.,Norwegian Institute of Public Health | Reichborn-Kjennerud T.,University of Oslo | Reichborn-Kjennerud T.,Columbia University | And 4 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2011

Background: The assessment of a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) life-time history of alcohol dependence (LTH-AD) has been found to be moderately reliable and substantially heritable. However, in studies of the heritability of LTH-AD, measurement error could not be discriminated from the true unique environmental effects. The aims of this study were to: (i) estimate the reliability of LTH-AD in a population based sample, (ii) identify characteristics of LTH-AD predicting a reliable diagnosis, (iii) investigate the heritability of LTH-AD as a function of diagnostic confidence, and (iv) to estimate the genetic and environmental influences on LTH-AD correcting for measurement error. Methods: An unselected sample of 4,203 male twins was interviewed twice approximately 1-year apart assessing DSM-IV LTH-AD over the same period of life. Logistic regression was used to identify clinical features that predict a reliable diagnosis LTH-AD. Genetic and environmental influences on reliable LTH-AD were examined using structural equation models. Results: Reliability of the diagnosis of LTH-AD was moderate (κ=0.54) and was predicted by the number of AD symptoms, treatment seeking, duration of most severe episode, and a great deal of time spent to obtain, use, or recover from alcohol use (DSM-IV AD criterion #5). Using an index of caseness, heritability of LTH-AD increased as a function of diagnostic confidence. Accounting for errors of measurement in a multivariate twin model, the heritability of LTH-AD increased from 55 to 71%. Conclusions: Reliably diagnosed LTH-AD can be predicted by characteristics relevant to the disorder. LTH-AD appears to be a moderately reliable disorder of high heritability. © 2011 by the Research Society on Alcoholism.


Chartier K.G.,Virginia Commonwealth University | Chartier K.G.,Virginia Institute for Psychiatric and Behavioral Genetics | Vaeth P.A.C.,Pacific Institute for Research and Evaluation | Caetano R.,University of Texas at Dallas
Alcohol Research: Current Reviews | Year: 2013

Alcohol consumption is differentially associated with social and health harms across U.S. ethnic groups. Native Americans, Hispanics, and Blacks are disadvantaged by alcohol-attributed harms compared with Whites and Asians. Ethnicities with higher rates of risky drinking experience higher rates of drinking harms. Other factors that could contribute to the different effects of alcohol by ethnicity are social disadvantage, acculturation, drink preferences, and alcohol metabolism. This article examines the relationship of ethnicity and drinking to (1) unintentional injuries, (2) intentional injuries, (3) fetal alcohol syndrome (FAS), (4) gastrointestinal diseases, (5) cardiovascular diseases, (6) cancers, (7) diabetes, and (8) infectious diseases. Reviewed evidence shows that Native Americans have a disproportionate risk for alcohol-related motor vehicle fatalities, suicides and violence, FAS, and liver disease mortality. Hispanics are at increased risk for alcohol-related motor vehicle fatalities, suicide, liver disease, and cirrhosis mortality; and Blacks have increased risk for alcohol-related relationship violence, FAS, heart disease, and some cancers. However, the scientific evidence is incomplete for each of these harms. More research is needed on the relationship of alcohol consumption to cancers, diabetes, and HIV/AIDS across ethnic groups. Studies also are needed to delineate the mechanisms that give rise to and sustain these disparities in order to inform prevention strategies.

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