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We examined how brain reserve in midlife, measured by brain-predicted age difference scores (Brain-PADs), predicted executive function concurrently and longitudinally into early old age, and whether these associations were moderated by young adult cognitive reserve or APOE genotype. 508 men in the Vietnam Era Twin Study of Aging (VETSA) completed neuroimaging assessments at mean age 56 and six executive function tasks at mean ages 56, 62, and 68 years. Results indicated that greater brain reserve at age 56 was associated with better concurrent executive function (r=.10, p=.040) and less decline in executive function over 12 years (r=.34, p=.001). These associations were not moderated by cognitive reserve or APOE genotype. Twin analysis suggested associations with executive function slopes were driven by genetic influences. Our findings suggest that greater brain reserve allowed for better cognitive maintenance from middle- to old age, driven by a genetic association. The results are consistent with differential preservation of executive function based on brain reserve that is independent of young adult cognitive reserve or APOE genotype., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging., Competing Interests: Disclosure statement L.K. McEvoy has stock options in CorTechs Laboratories, Inc. A.M. Dale is a founder of and holds equity in CorTechs Laboratories, Inc and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by University of California, San Diego in accordance with conflict of interest policies. The remaining authors disclose no conflicts., (Published by Elsevier Inc.)

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals., (Copyright © 2021. Published by Elsevier Inc.)

Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. AD polygenic risk scores (AD-PRSs) are associated with increased odds of AD and mild cognitive impairment (MCI). Additional sources of genetic risk may also contribute to disease outcomes. Coronary artery disease (CAD) is a risk factor for AD, interacts with AD pathology, and is also heritable. We showed that incidence-based and prevalence-based CAD-PRSs moderate the association between the AD-PRS and MCI, but in opposing directions. Higher incidence-based CAD-PRSs interacted with the AD-PRS to further increase MCI risk. Conversely, the AD-PRS was predictive of MCI when prevalence-based CAD-PRSs were low. The latter finding is likely due to prevalent CAD cases being biased toward longer postevent survival times, perhaps selecting for protective loci that offset AD risk. These results demonstrate (1) the importance of examining multiple PRSs and their interactions; (2) how genetic risk for one disease can modify the impact of genetic risk for another; and (3) the importance of considering ascertainment procedures of GWAS used for genetic risk prediction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Locus coeruleus (LC) tau accumulation begins early. Targeting LC (dys)function might improve early identification for Alzheimer's disease (AD) risk. Pupillary responses during cognitive tasks are driven by the LC and index cognitive effort. Despite equivalent task performance, adults with mild cognitive impairment have greater pupil dilation/effort during digit span than cognitively normal (CN) individuals. We hypothesized that AD polygenic risk scores (AD-PRSs) would be associated with pupillary responses in middle-aged CN adults. Pupillary responses during digit span tasks were heritable (h 2  = 0.30-0.36) in 1119 men aged 56-66 years. In a CN subset-all with comparable span capacities (n = 539)-higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit) cognitive load condition (Cohen's d = 0.36 for upper vs. lower quartile of AD-PRS distribution). Results held up after controlling for APOE genotype. Results support pupillary response-and by inference, LC dysfunction-as a genetically mediated biomarker of early mild cognitive impairment/AD risk. In combination with other biomarkers, task-evoked pupillary responses may provide additional information for early screening of genetically at-risk individuals even before cognitive declines., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Youth with psychiatric disorders distinguished by irritability, including depression and associated trait neuroticism, show deficits in the ability to recognize facial expressions of emotion, particularly happiness. However, the contribution of genetic and environmental factors to this ability remains unknown. The present study examined this trait in twins to assess the genetic and environmental influences on face-emotion recognition abilities and their association with irritability, neuroticism, and depression., Method: Child and adolescent twins (N = 957 from 496 families) 9 to 17 years old rated their irritability (on the Affective Reactivity Index), neuroticism (on the Junior Eysenck Personality Questionnaire), and depression (on the Short Mood and Feelings Questionnaire) and completed a face-emotion labeling task. Faces depicting anger, disgust, fear, happiness, sadness, and surprise were morphed with a neutral face, yielding 10 levels of increasing emotional expressivity. Biometrical twin analyses evaluated contributions of genetic and environmental factors to the etiology of face-emotion recognition and its association with irritability, neuroticism, and depression., Results: Recognition of each emotion was heritable; common and specific sets of genetic factors influenced all emotions and individual emotions, respectively. Irritability, neuroticism, and depression were modestly and negatively correlated with emotion recognition, particularly the recognition of happiness. For irritability and neuroticism, this correlation appeared largely due to genetic factors., Conclusion: This study maps genetic and environmental contributions to face-emotion recognition and its association with irritability, neuroticism, and depression. Findings implicate common genetic factors in deficits regarding the recognition of happiness associated with irritability and neuroticism in childhood and adolescence., (Copyright © 2018 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

The ABCD twin study will elucidate the genetic and environmental contributions to a wide range of mental and physical health outcomes in children, including substance use, brain and behavioral development, and their interrelationship. Comparisons within and between monozygotic and dizygotic twin pairs, further powered by multiple assessments, provide information about genetic and environmental contributions to developmental associations, and enable stronger tests of causal hypotheses, than do comparisons involving unrelated children. Thus a sub-study of 800 pairs of same-sex twins was embedded within the overall Adolescent Brain and Cognitive Development (ABCD) design. The ABCD Twin Hub comprises four leading centers for twin research in Minnesota, Colorado, Virginia, and Missouri. Each site is enrolling 200 twin pairs, as well as singletons. The twins are recruited from registries of all twin births in each State during 2006-2008. Singletons at each site are recruited following the same school-based procedures as the rest of the ABCD study. This paper describes the background and rationale for the ABCD twin study, the ascertainment of twin pairs and implementation strategy at each site, and the details of the proposed analytic strategies to quantify genetic and environmental influences and test hypotheses critical to the aims of the ABCD study., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A clearer understanding of the etiological overlap between DSM-IV personality disorders (PDs) and alcohol use (AU) and alcohol use disorder (AUD) is needed. To our knowledge, no study has modeled the association between all 10 DSM-IV PDs and lifetime AU and AUD. The aim of the present study is to identify which PDs are most strongly associated with the phenotypic, genetic, and environmental risks of lifetime AU and AUD, and to determine if these associations are stable across time., Methods: Participants were Norwegian twins assessed at two waves. At Wave 1, 2801 twins were assessed for all 10 DSM-IV PD criteria, lifetime AU, and DSM-IV AUD criteria. At Wave 2, six of the 10 PDs were again assessed along with AU and AUD among 2393 twins. Univariate and multiple logistic regressions were run. Significant predictors were further analyzed using bivariate twin Cholesky decompositions., Results: Borderline and antisocial PD criteria were the strongest predictors of AU and AUD across the two waves. Despite moderate phenotypic and genetic correlations, genetic variation in these PD criteria explained only 4% and 3% of the risks in AU, and 5% to 10% of the risks in AUD criteria, respectively. At Wave 2, these estimates increased to 8% and 23% for AU, and 17% and 33% for AUD., Conclusions: Among a large Norwegian twin sample, borderline and antisocial PD criteria were the strongest predictors of the phenotypic and genotypic liability to AU and AUD. This effect remained consistent across time., (Copyright © 2017 Elsevier B.V. All rights reserved.)

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E- ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age ( t  = 1.9, p  = 0.05) and hypertension ( t  = 2.9, p  = 0.004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled ( t  = 3.0, p  = 0.003) and normotensive ( t  = 4.0, p  = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a 2  = 0.81) and shared some genetic influences with systolic blood pressure (r A  = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery.

Objective: In an effort to address earliest detection of mild cognitive impairment (MCI), we examined hippocampal volumes and atrophy in middle-aged men to explore neuroanatomical support for different neuropsychological definitions of MCI., Methods: 460 men aged 51-60 years underwent neuropsychological testing and MRI. MCI was defined according to five criteria sets. MRI-derived hippocampal volume and hippocampal occupancy (HOC) were obtained via FreeSurfer. Statistical analyses were performed using linear mixed models., Results: Differences in HOC between normal cognitive functioning, amnestic, and non-amnestic MCI were observed using MCI criteria that required one impaired (>1.5 SD) cognitive measure in a given cognitive domain or a cognitive composite score method with a cut-point 2 SD below the mean. Differences in standard hippocampal volume were only found between normal and amnestic presentations and only when using the composite score method., Conclusion: Results provide empirical support for detection of pre-MCI in younger cohorts. Convergence of neuropsychological and neuroanatomical data, particularly HOC (as opposed to standard cross-sectional volume), supports early identification of MCI as defined by some neuropsychological criteria., (Published by Elsevier Inc.)

This review describes how improvements in biometric-genetic studies of twin kinships, half-sibships, and cousinships have now demonstrated a sizeable fetal genetic and maternal genetic contribution to the spontaneous onset of labor. This is an important development because previous literature for the most part reports only an influence of the maternal genome. Current estimates of the percent of variation that is attributable to fetal genetic factors range from 11-35%; the range for the maternal genetic contribution is 13-20%. These same studies demonstrate an even larger influence of environmental sources over and above the influence of genetic sources and previously identified environmental risk factors. With these estimates in hand, a major goal for research on pregnancy duration is to identify specific allelic variation and environmental risk to account for this estimated genetic and environmental variation. A review of the current literature can serve as a guide for future research efforts., (Published by Mosby, Inc.)

Aims: 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., Design: 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., Participants: 1796 males aged 24-63 from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders., Measurements: 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., Findings: 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., Conclusion: 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., (Published by Elsevier Ireland Ltd.)

Background: Two competing concepts address the development of involvement with psychoactive substances: the "gateway hypothesis" (GH) and common liability to addiction (CLA)., Method: The literature on theoretical foundations and empirical findings related to both concepts is reviewed., Results: The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations., Conclusions: Whereas the "gateway" hypothesis does not specify mechanistic connections between "stages", and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non-drug-specific prevention and early intervention., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Twin studies generally show great consistency for the heritability of brain structures. Ironically, the lateral ventricles--perhaps the most reliably measured brain regions of interest--are the most inconsistent when it comes to estimating genetic influences on their volume. Heritability estimates in twin studies have ranged from zero to almost 0.80. Here we aggregate heritability estimates from extant twin studies, and we review and reinterpret some of the findings. Based on our revised estimates, we conclude that lateral ventricular volume is indeed heritable. The weighted average heritability of the revised estimates was 0.54. Although accumulated environmental insults might seem most logical as the predominant cause of age-related ventricular expansion, the data strongly suggest that genetic influences on lateral ventricular volume are increasing with age. Genetic influences accounted for 32-35% of the variance in lateral ventricular volume in childhood, but about 75% of the variance in late middle and older age. These conclusions have implications for the basic understanding of the genetic and environmental underpinnings of normative and pathological brain aging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Despite an emerging consensus that the DSM-IV diagnostic criteria for cannabis abuse and dependence are best represented by a single underlying liability, it remains unknown if latent class or hybrid models can better explain the data., Method: Using structured interviews, 7316 adult male and female twins provided complete data on DSM-IV symptoms of cannabis abuse and dependence. Our aim was to derive a parsimonious, best-fitting cannabis use disorder (CUD) phenotype based on DSM-III-R/IV criteria by comparing an array of psychometric models (latent factor analysis, latent class analysis and factor mixture modeling) using full information maximum likelihood ordinal data methods in Mx., Results: We found little evidence to support population heterogeneity since neither latent class nor hybrid factor mixture models provided a consistently good fit to the data. When conditioned on initiation and cannabis use, the endorsement patterns of the abuse, dependence and withdrawal criteria were best explained by two latent factors for males and females. The first was a general CUD factor for which genetic effects explained 53-54% of the variance. A less interpretable second factor included a mix of cross-loading dependence and withdrawal symptoms., Conclusions: This is the first study to compare competing measurement models to derive an empirically determined CUD phenotype. Commensurate with proposed changes to substance use disorders in the DSM-V, our results support an emerging consensus that a single CUD latent factor can more optimally assess the risk or liability underpinning correlated measures of use, abuse, dependence and withdrawal criterion., (Published by Elsevier Ireland Ltd.)

Objective: To describe the utility of twin studies for attention-deficit/hyperactivity disorder (ADHD) research and demonstrate their potential for the identification of alternative phenotypes suitable for genomewide association, developmental risk assessment, treatment response, and intervention targets., Method: Brief descriptions of the classic twin study and genetic association study methods are provided, with illustrative findings from ADHD research. Biometrical genetics refers to the statistical modeling of data gathered from one or more group of known biological relation; it was apparently coined by Francis Galton in the 1860s and led to the "Biometrical School" at the University of London. Twin studies use genetic correlations between pairs of relatives, derived using this theoretical framework, to parse the individual differences in a trait into latent (unmeasured) genetic and environmental influences. This method enables the estimation of heritability, i.e., the percentage of variance due to genetic influences. It is usually implemented with a method called structural equation modeling, which is a statistical technique for fitting models to data, typically using maximum likelihood estimation. Genetic association studies aim to identify those genetic variants that account for the heritability estimated in twin studies. Measurements other than those used for the clinical diagnosis of the disorder are popular phenotype choices in current ADHD research. It is argued that twin studies have great potential to refine phenotypes relevant to ADHD., Results: Prior studies have consistently found that the majority of the variance in ADHD symptoms is due to genetic factors. To date, genomewide association studies of ADHD have not identified replicable associations that account for the heritable variation. Possibly, the application of genomewide association studies to these alternative phenotypic measurements will assist in identifying the pathways from genetic variants to ADHD., Conclusion: Power to detect associations should be improved by the study of highly heritable endophenotypes for ADHD and by reducing the number of phenotypes to be considered. Therefore, twin studies are an important research tool in the development of endophenotypes, defined as alternative, more highly heritable traits that act at earlier stages of the pathway from genes to behavior. Although genetic variation in liability to ADHD is likely polygenic, the proposed approach should help to identify improved alternative measurements for genetic association studies., (2010 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally specific sets of genes., Methods: We mapped the heritability of cortical thickness throughout the brain using three-dimensional structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface., Results: There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions., Conclusions: These results provide strong evidence of regionally specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders and normal and pathological cognitive aging., (Copyright 2010 Society of Biological Psychiatry. All rights reserved.)

The relative influence of genetics and the environment on factors associated with cardiovascular disease (CVD) and metabolic syndrome (MetS) remains unclear. We performed model-fitting analyses to quantify genetic, common environmental, and unique environmental variance components of factors associated with CVD and MetS [waist circumference, blood pressure, fasting plasma glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and fasting plasma lipids] in adult male and female monozygotic twins reared apart or together. We also investigated whether MetS components share common influences. Plasma cholesterol and triglyceride concentrations were highly heritable (56-77%, statistically significant). Waist circumference, plasma glucose and insulin, HOMA-IR, and blood pressure were moderately heritable (43-57%, statistically significant). Unique environmental factors contributed to the variance of all variables (20-38%, perforce statistically significant). Common environmental factors contributed 23, 30, and 42% (statistically significant) of the variance of waist circumference, systolic blood pressure, and plasma glucose, respectively. Two shared factors influenced MetS components; one influenced all components except HDL cholesterol, another influenced only lipid (triglyceride and HDL cholesterol) concentrations. These results suggest that genetic variance has a dominant influence on total variance of factors associated with CVD and MetS and support the proposal of one or more underlying pathologies of MetS.

Alcohol dependence (AD) is a complex and heterogeneous disorder. The identification of more homogeneous subgroups of individuals with drinking problems and the refinement of the diagnostic criteria are inter-related research goals. They have the potential to improve our knowledge of etiology and treatment effects, and to assist in the identification of risk factors or specific genetic factors. Mixture modeling has advantages over traditional modeling that focuses on either the dimensional or categorical latent structure. The mixture modeling combines both latent class and latent trait models, but has not been widely applied in substance use research. The goal of the present study is to assess whether the AD criteria in the population could be better characterized by a continuous dimension, a few discrete subgroups, or a combination of the two. More than seven thousand participants were recruited from the population-based Virginia Twin Registry, and were interviewed to obtain DSM-IV (Diagnostic and Statistical Manual of Mental Disorder, version IV) symptoms and diagnosis of AD. We applied factor analysis, latent class analysis, and factor mixture models for symptom items based on the DSM-IV criteria. Our results showed that a mixture model with 1 factor and 3 classes for both genders fit well. The 3 classes were a non-problem drinking group and severe and moderate drinking problem groups. By contrast, models constrained to conform to DSM-IV diagnostic criteria were rejected by model fitting indices providing empirical evidence for heterogeneity in the AD diagnosis. Classification analysis showed different characteristics across subgroups, including alcohol-caused behavioral problems, comorbid disorders, age at onset for alcohol-related milestones, and personality. Clinically, the expanded classification of AD may aid in identifying suitable treatments, interventions and additional sources of comorbidity based on these more homogenous subgroups of alcohol use problems.

Background: Catechol-O-methyltransferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits., Methods: We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic risk factor shared by neuroticism, several anxiety disorders, and major depression from a large population-based twin sample. With one member from each of these pairs, the resulting sample of 589 cases and 539 control subjects were entered into a two-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2., Results: The functional val158met polymorphism (rs4680) plus nine other single nucleotide polymorphism markers selected to capture the major allelic variation across the COMT locus were analyzed for differences between cases and control subjects. Although the val (G) allele of rs4680 showed marginally significant association in our combined stage 1 plus stage 2 sample, a high-risk haplotype of this allele with the A allele of rs165599 was significantly over-represented in cases (p = 1.97e-5, odds ratio = 1.95). This haplotype also predicted individual differences in neuroticism and risk for several anxiety disorders and major depression. Consistent with prior studies, our findings are female-specific., Conclusions: Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes.

Background: Several lines of evidence suggest that the clinical heterogeneity of schizophrenia is due to genetic heterogeneity. Genetic heterogeneity may decrease the signal-to-noise ratio in linkage and association studies. Therefore, linkage studies of clinically homogeneous classes of psychotic illness may result in greater power to detect at least some loci., Methods: Latent class analysis was used to divide psychotic subjects from 270 Irish high-density families (N = 755) into six classes based on the Operational Criteria Checklist for Psychotic Illness. We heuristically call them Bipolar, Schizoaffective, Mania, Schizomania, Deficit Syndrome, and Core Schizophrenia. The latter four had prevalences of greater than .08 and were individually tested for linkage in a 10-cM nonparametric autosomal genomewide scan. Empirical significance was determined using 200 simulated genome scans., Results: Seven regions achieved empirical criteria for suggestive significance for at least one latent class: 5q23.2-q35.3, 8q13.1-q23.1, 10q23.33-q26.3, 12q21.2-q24.32, 19q13.32-q13.43, 20p13-q22.3, and 21q11.2-q22.3. Five of 200 simulated scans resulted in seven suggestively significant loci (experiment-wide p = .03). Furthermore, at 20p13-p12.2, the Mania and Schizomania classes individually achieved criteria, whereas Deficit Syndrome had a suggestive logarithm of the odds peak 28 cM centromeric to this locus., Conclusions: Using empirically derived, clinically homogeneous phenotypes, four chromosomal regions were suggestively linked but provided little evidence of linkage using traditional operationalized criteria. This approach was particularly fruitful on chromosome 20, which had previously yielded little evidence of linkage. Future studies of psychiatric illness may increase their ability to detect linkage or association by using clinically homogeneous phenotypes.

Background: Fear conditioning is a traditional model for the acquisition of phobias, whereas behavioral therapies use processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. Although prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis., Methods: We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. With multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation., Results: Phenotypic correlations between experimental and self-report fear measures were modest and, counter-intuitively, negative (i.e., subjects who reported themselves as more fearful had smaller electrophysiologic responses). Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears., Conclusions: Experimentally derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders.

Background: A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses., Methods: We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped in all subjects. The phenotypes analyzed were the Fagerström Test for Nicotine Dependence (FTND), a history of nicotine dependence, the number of symptoms of alcohol dependence (AlcSx), and a history of alcohol dependence. Genomewide linkage analyses were conducted with non-parametric and variance components methods., Findings: For the bivariate variance component analysis of the continuous FTND and AlcSx scores, multipoint LOD scores were >4 in two genomic regions--an 11cM region on chr7 (D7S2252-D7S691, empirical p=0.0006) and an 8cM region on chr18 flanking D18S63 (empirical p=0.0007). These findings did not exceed a conservative estimate of study-wide significance. The remaining sets of findings had considerably smaller or less consistent peak signals. Notably, strong linkage signal at D4S1611 for AlcSx from a prior report (PMID 16534506) was not found when jointly analyzed with FTND., Interpretation: Replication is required. However, chromosomes 7 and 18 may contain genetic loci relevant to the etiology of nicotine-related phenotypes.

Background: Knowledge regarding the causes of comorbidity among substance use disorders can have significant impact on future research examining the etiology of these disorders. Unfortunately, the conclusions of past studies examining the comorbidity among substance use disorders are conflicting; some studies emphasize familial influences common to multiple substances, while others emphasize substance-specific influences. Discrepancies in results may reflect different analytical approaches or differences in the samples. Here, we examine the causes of comorbidity between alcohol dependence and illicit drug dependence in adolescents., Methods: We ascertained a clinical sample of adolescents treated for antisocial behavior and substance use disorders and their siblings and a matched control sample. A model fitting approach was used to test 13 alternative hypotheses for the causes of comorbidity., Results: The best supported hypothesis for the comorbidity between alcohol dependence and illicit drug dependence was a model hypothesizing that comorbid disorders are alternate forms of a single underlying liability. The next best fitting models were two of the correlated liabilities models (correlated risk factors and reciprocal causation)., Discussion: The results suggest that the best hypotheses explaining the comorbidity between alcohol and illicit drug dependence in adolescents are that alcohol dependence and illicit drug dependence are manifestations of a single general liability to develop substance dependence or that there are separate liabilities that are highly correlated.

Background: We undertook this study to determine whether the widely replicated link between maternal smoking and conduct disturbance (Cd) is better explained by a model of direct causation or of mother-offspring transmission of a latent Cd variable., Methods: Family data collected on 538 adolescent twin boys from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) was used to compare two alternative models: 1) a model composed of a latent transmissible factor that influences mother's juvenile conduct symptoms, smoking during pregnancy, and subsequent Cd and smoking in her adolescent boys; and 2) a model specifying a direct causal path from mother's smoking to child Cd., Results: The maternal-offspring transmission model fit the data as well as a model specifying a direct causal path from maternal smoking to child Cd., Conclusions: Our results suggest that the association between maternal smoking during pregnancy and boys' Cd symptoms may be attributed to the transmission of a latent Cd factor and not to a direct effect of the smoking. Our results challenge previous findings of a direct effect of prenatal smoke exposure on risk to Cd once other etiologic factors are considered.

Objective: To estimate genetic, environmental, and rater contrast influences on parental report of Attention Problems (AP), Aggressive (Agg), and Anxious/Depressed (AxD) behaviors of 492 twin pairs assessed with the Child Behavior Checklist., Method: A parent (92% mothers) of twins aged 8 to 12 years completed the Child Behavior Checklist. Genetic, shared and unique environmental, and rater bias effects were estimated for the AP, Agg, and AxD syndromes. Data on boys and girls were analyzed separately. Results were compared to prior research on related DSM disorders., Results: Estimates of genetic influences on AP (60%-68%), Agg (70%-77%), and AxD (61%-65%) were high for both sexes, but lower for AP than prior findings using DSM attention-deficit hyperactivity disorder (ADHD). However, unlike equivalent analyses of DSM ADHD based on parental report, there was no evidence of rater bias., Conclusions: Estimates of genetic influence on these common child psychopathological domains were high. There was no evidence of rater contrast effects. These findings have implications for diagnosis, particularly when assessing families with multiple children.

Twins were recruited through alcohol and drug treatment programs. With structural equation modeling, genetic and environmental estimates were obtained for use and DSM-III abuse/dependence of sedatives, opioids, cocaine, stimulants, and cannabis as well as any illicit drug. Analyses were conducted separately for males and females. Models included thresholds based on population prevalence of use or abuse/dependence and ever having been in treatment. Genetic influences were found for most measures. They were generally stronger for males than females and for clinical diagnoses of abuse/dependence compared to use. Common environmental influences played a greater role in use than abuse/dependence.

Background: Research into genes involved in alcoholism could benefit from use of diagnostic systems most sensitive to detecting genetic influences. In this study, heritable influences were estimated in a single twin sample with commonly used criteria for alcoholism., Methods: Male twin probands ascertained through alcohol and drug abuse treatment programs and their same-sex cotwins (54 monozygotic and 65 dizygotic pairs) were diagnosed independently by DSM-III (alcohol dependence and alcohol abuse and/or dependence), Feighner (probable and definite alcoholism), and Cloninger (type 1 and type 2 alcoholism) systems. Using univariate structural equation modeling, heritability was estimated for each diagnostic system., Results: The highest heritability estimates were obtained for Feighner probable alcoholism (h2 = .63), Cloninger type 2 alcoholism (h2 = .54), and DSM-III alcohol dependence (h2 = .52)., Conclusions: Certain diagnostic systems appear to have greater sensitivity for detecting genetic influence and may therefore be more appropriate for use in molecular genetic studies attempting to find genes for alcoholism.

Assortative mating can exert a profound influence on the phenotypic composition of the population since it may result in an increase in the frequency of the genotypes associated with extreme phenotypes. Applied to the risk for a disorder such as substance abuse, this would mean a possibility for an increase in the risk and severity of the disorder in consecutive generations. This paper reviews the theoretical and empirical literature on mechanisms related to mate resemblance for the liability to substance abuse, sources and consequences of such resemblance, and suggests directions for further research.

Food and water consumption were measured in rats prior to and during a course of antidepressant drug administration. Desmethylimipramine (DMI, 10 mg/kg/day), clorgyline (1.0 mg/kg/day) or saline were injected IP for 30 days. Food and water intake in the DMI- and clorgyline-treated rats was initially and significantly decreased but progressively returned towards pretreatment levels over the course of the drug administration. The effects of these antidepressant drug treatments on food and water intake appeared to consist of two components: (a) a rapid suppressive effect, possibly associated with an acute central action of these drugs (and perhaps a slight initial stress effect related to the drug administration) and (b) an adaptive effect over the course of the treatment which may involve changes in monoaminergic neurotransmitters or receptor status in those brain regions associated with feeding behavior. The similarities of the results of these treatments and those seen with chronic stress are discussed.