Brain Abnormalities in Patients with Germline Variants in H3F3: Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors.

BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.

Heritable influences on amygdala and orbitofrontal cortex contribute to genetic variation in core dimensions of personality.

While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55 years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (r(p)) and genetic (r(g)) correlations were observed between left amygdala volume and positive emotionality (r(p)=.16, p<.01; r(g)=.23, p<.05, respectively). In addition, after adjusting for mean cortical thickness, genetic and nonshared-environmental correlations (r(e)) between left medial orbitofrontal cortex thickness and negative emotionality were also observed (r(g)=.34, p<.01; r(e)=-.19, p<.05, respectively). These findings support a model positing that heritable bases of personality are, at least in part, mediated through individual differences in the size of brain structures, although further work is still required to confirm this causal interpretation.

A multivariate twin study of hippocampal volume, self-esteem and well-being in middle-aged men.

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.

Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men.

BACKGROUND: The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle age. METHODS: Participants were men from the Vietnam Era Twin Study of Aging (n = 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data. RESULTS: A significant interaction was observed between testosterone and APOE genotype (epsilon4-negative vs epsilon4-positive). Those with both low testosterone (> or =1 SD below the mean) and an epsilon4-positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and epsilon4-negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-by-testosterone interaction was present. CONCLUSIONS: These findings demonstrate an interaction effect between testosterone and the APOE epsilon4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production.

Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome.

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Apolipoprotein E genotype and memory in the sixth decade of life.

BACKGROUND: Virtually all adult studies of APOE genotypes and cognition have included individuals over 60. In older adults, epsilon 4 carriers may manifest greater cognitive asymmetries than non-epsilon 4 carriers even in the absence of overall mean differences. General cognitive ability may also be affected by aging and APOE genotype, but most studies have inadequately addressed this potential confound. The goals of this study were to examine, in middle age, the relationship of APOE genotype with episodic memory and verbal-visuospatial episodic memory asymmetries, after accounting for prior general cognitive ability. METHOD: We compared epsilon 4+ and epsilon 4- individuals in 626 male twins in their 50s. We examined verbal and visuospatial episodic memory and verbal-visual asymmetry scores after adjusting for cognitive ability at age 20. Analyses corrected for correlations between twin pair members. RESULTS: Compared with epsilon 4- individuals, epsilon 4 carriers performed significantly more poorly on verbal, but not visuospatial memory, manifested significantly greater cognitive asymmetry, and also had significantly more concerns about memory. At age 20, epsilon 4 carriers had higher general cognitive ability than epsilon 4- individuals, and current memory differences were enhanced after adjusting for age 20 cognitive ability. CONCLUSIONS: Small, but significant, APOE-epsilon 4-related memory deficits appear in the sixth decade of life in individuals who show no signs of preclinical dementia. The results partially support studies of older adults that suggest that increased cognitive asymmetries reflect risk for dementia and are associated with the APOE-epsilon 4 genotype. The results also highlight the potential problems of not having accurate data on prior cognitive ability.

Educational attainment, smoking initiation and lifetime nicotine dependence among male Vietnam-era twins.

BACKGROUND: Smoking initiation and persistence are clearly associated with factors commonly thought to be environmental in origin, including socio-economic status. However, twin models that incorporate gene-environment correlation and gene x environment interaction have not been applied to elucidate the genetic or environmental role that socio-economic status plays in smoking initiation and nicotine dependence. METHOD: Twin structural equation modelling was used to examine gene-environment correlation and gene x environment interaction of one index of socio-economic status, educational attainment, with smoking initiation and nicotine dependence among 5119 monozygotic and 4295 dizygotic male-male Vietnam-era twins from the Vietnam Era Twin Registry, a national registry of twin pairs who served in the military during the Vietnam era. RESULTS: Educational attainment correlated significantly with smoking initiation (r=-0.27, p<0.001). Additive genetic (p=0.011), shared environment (p=0.002) and unique environment (p=0.027) components contributed to the correlation between educational attainment and smoking initiation. Educational attainment also significantly moderated the variance in smoking initiation (p<0.001), suggestive of gene x environment interaction, although the interaction with the additive genetic, shared environmental and unique environmental components could not be resolved due to multi-collinearity. In contrast, educational attainment neither correlated with nor moderated nicotine dependence, once smokers had initiated. CONCLUSIONS: Our study suggests that educational attainment is associated with smoking initiation, in part due to gene-environment correlation and gene x environment interaction. However, once smoking initiation is taken into account, there are no effects--be they gene-environment correlation or gene x environmental interaction--of educational attainment on nicotine dependence.

Neuropsychological consequences of regular marijuana use: a twin study.

BACKGROUND: Results of previous research examining long-term residual effects of marijuana use on cognition are conflicting. A major methodological limitation of prior studies is the inability to determine whether differences between users and non-users are due to differences in genetic vulnerability preceding drug use or due to the effects of the drug. METHOD: Fifty-four monozygotic male twin pairs, discordant for regular marijuana use in which neither twin used any other illicit drug regularly, were recruited from the Vietnam Era Twin Registry. A minimum of 1 year had passed since the marijuana-using twins had last used the drug, and a mean of almost 20 years had passed since the last time marijuana had been used regularly. Twins were administered a comprehensive neuropsychological test battery to assess general intelligence, executive functioning, attention, memory and motor skills. Differences in performance between marijuana-using twins and their non-using co-twins were compared using a multivariate analysis of specific cognitive domains and univariate analyses of individual test scores. Dose response relationships were explored within the marijuana-using group. RESULTS: Marijuana-using twins significantly differed from their non-using co-twins on the general intelligence domain; however, within that domain only the performance of the block design subtest of the Wechsler Adult Intelligence Scale--Revised reached a level of statistical significance. CONCLUSIONS: Out of the numerous measures that were administered, only one significant difference was noted between marijuana-using twins and their non-using co-twins on cognitive functioning. The results indicate an absence of marked long-term residual effects of marijuana use on cognitive abilities.

A twin study of genetic and environmental influences on suicidality in men.

BACKGROUND: Previous studies that have examined genetic influences on suicidal behaviour were confounded by genetic vulnerability for psychiatric risk factors. The present study examines genetic influences on suicidality (i.e. suicidal ideation and/or suicide attempt) after controlling for the inheritance of psychiatric disorders. METHODS: Sociodemographics, combat exposure, lifetime DSM-III-R major depression, bipolar disorder, childhood conduct disorder, adult antisocial personality disorder, panic disorder, post-traumatic stress disorder, drug dependence, alcohol dependence and lifetime suicidal ideation and attempt were assessed in 3372 twin pairs from the Vietnam Era Twin Registry who were assessed in 1987 and 1992. Genetic risk factors for suicidality were examined in a multinomial logistic regression model. Additive genetic, shared environmental and non-shared environmental effects on suicidality were estimated using structural equation modelling, controlling for other risk factors. RESULTS: The prevalence of suicidal ideation and suicide attempt were 16.1% and 2.4% respectively. In a multinomial regression model, co-twin's suicidality, being white, unemployment, being other than married, medium combat exposure and psychiatric disorders were significant predictors for suicidal ideation. Co-twin's suicidality, unemployment, marital disruption, low education attainment and psychiatric disorders (except childhood conduct disorder) were significant predictors for suicide attempt. Model-fitting suggested that suicidal ideation was influenced by additive genetic (36%) and non-shared environmental (64%) effects, while suicide attempt was affected by additive genetic (17%), shared environmental (19%) and non-shared environmental (64%) effects. CONCLUSIONS: There may be a genetic susceptibility specific to both suicidal ideation and suicide attempt in men, which is not explained by the inheritance of common psychiatric disorders.

The Harvard Twin Study of Substance Abuse: what we have learned.

The Harvard Twin Study of Substance Abuse was carried out with the members of the Vietnam Era Twin (VET) Registry. The VET Registry comprises over 8000 male twins who served in the United States military between 1965 and 1975 and were subsequently interviewed regarding their use of licit and illicit substances, as well as various types of psychopathology. Our research has demonstrated significant influences by genetic, shared environmental, and unique environmental factors on the abuse of illicit substances. Multivariate analyses have indicated that the co-occurrence of abuse of various types of illicit drugs reflects a common vulnerability, influenced by both genetic and environmental factors, that cuts across all categories of illicit drugs. We have also demonstrated that some drugs have unique determinants, both genetic and environmental, that are not shared with other drugs. In part, the genetic influence on marijuana abuse is mediated by genetic influence on subjective effects in response to the drug. The determinants of transitions from one stage of drug use to another differ depending on which drug or which transition is examined. We determined significant genetic influences on several aspects of nicotine and alcohol use separately, as well as genetic influences shared by both substances. We found that the co-occurrence of illicit drug abuse and major depression is due to unique environmental influences. The phenotypic association between symptoms of conduct disorder and alcohol and marijuana dependence is due largely to shared environmental influences. Our results, thus far, indicate a complex pattern of genetic and environmental influences on substance use and abuse.

A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men.

Generalized anxiety disorder (GAD), panic disorder (PD) and post-traumatic stress disorder (PTSD) often co-occur. We investigated whether and to what degree genetic and environmental contributions overlap among symptoms of GAD, symptoms of PD and PTSD. Subjects were 3327 monozygotic and dizygotic male-male twin pair members of the Vietnam Era Twin Registry who participated in a 1992 telephone administration of the Diagnostic Interview Schedule Version 3 Revised (DIS3R). Genetic model fitting was performed to estimate the magnitude of genetic and environmental contributions to the lifetime co-occurrence of GAD symptoms, PD symptoms and PTSD. The liability for GAD symptoms was due to a 37.9% additive genetic contribution common to PD symptoms and PTSD. Liability for PD symptoms was due to a 20.7% additive genetic contribution common to GAD symptoms and PTSD, and a 20.1% additive genetic influence specific to PD symptoms. Additive genetic influences common to symptoms of GAD and PD accounted for 21.3% of the genetic variance in PTSD. Additive genetic influences specific to PTSD accounted for 13.6% of the genetic variance in PTSD. Remaining variance for all three disorders was due to unique environmental factors both common and specific to each phenotype. These results suggest that these disorders each have etiologically distinct components and also have significant genetic and unique environmental contributions in common.

The genetics of pathological gambling.

Problem and pathological gambling (PG) occurs in about 5% of Americans. Gambling is associated with substantial psychosocial and psychiatric health problems, and the increasing ease of access to gambling may increase its future prevalence. Therefore, it is important to gain greater insight into the causes of PG. Family studies of PG are consistent with a substantial familial impact on vulnerability to PG. However, family studies cannot distinguish genetic from family environmental influences. By contrast, the study of twin pairs permits the genetic and environmental influences on PG to be estimated. The study of gambling behavior among 3,359 twin pair members of the Vietnam Era Twin Registry suggests that: (1) inherited factors explain a substantial proportion of the variance in the report of symptoms of gambling; (2) there is a single continuum of genetic vulnerability that underlies gambling problems of varying severities; and, (3) the co-occurrence of PG with conduct disorder, antisocial personality disorder, and alcohol abuse/dependence is partially explained by genes that influence both PG and these other psychiatric disorders. Neurophysiological correlates of gambling problems and genetically based differences in neurotransmitter systems may provide biological mechanisms that explain the genetic basis for a predisposition to PG.

Genetic and environmental influences on the relationship among combat exposure, posttraumatic stress disorder symptoms, and alcohol use.

The role of genetic and environmental influences on the relationship between combat exposure, posttraumatic stress disorder (PTSD) symptoms, and alcohol use were examined in 4072 male-male twin pairs who served in the United States military during the Vietnam era (1965-1975). Results indicate that the relationship between combat and alcohol use and between PTSD symptom factors and alcohol use were both substantially influenced by genetic factors. Findings are most consistent with a shared vulnerability model for the etiology of the association between PTSD symptoms and alcohol use. Specific unique environmental factors were more important than genetic factors for PTSD symptoms, and both factors were equally important for alcohol use. Further support is also found for the role of the unique environment in PTSD symptoms.

A twin study of the association between pathological gambling and antisocial personality disorder.

Many individuals with a history of pathological gambling (PG) also have a history of engaging in antisocial behaviors, and this has often been interpreted as a result of the former causing the latter. In a sample of 7,869 men in 4,497 twin pairs from the Vietnam Era Twin Registry, the authors examined (a) the association between PG and antisocial personality disorder (ASPD), (b) the extent to which PG might be differentially associated with childhood conduct disorder (CD) and adult antisocial behavior (AAB), and (c) the contribution of genetic and environmental factors to the association of PG with ASPD, CD, and AAB. PG was significantly associated with all 3 antisocial behavior disorders, and the association of PG with ASPD, CD, and AAB was predominantly explained by genetic factors. The results of this study suggest that the greater-than-chance co-occurrence of PG and antisocial behavior disorders is partially due to their sharing a common genetic vulnerability. The antisocial behavior observed among many individuals with PG probably cannot be interpreted as being simply a consequence of the PG.

Heritability of self-reported health.

OBJECTIVE: To explore the contribution of genes and environmental factors to variation in a common measure (i.e., a five-point--excellent, very good, good, fair, and poor--Likert scale) of self-reported health. DATA SOURCES: Data were analyzed from 4,638 male-male twin pair members of the Vietnam Era Twin (VET) Registry who responded to a 1987 health survey. STUDY DESIGN: Varying models for the relationship between genetic and environmental influences on self-reported health were tested in an attempt to explain the relative contributions of additive genetic, shared and nonshared environmental effects, and health conditions reported since 1975 to perceived health status. DATA COLLECTION: A mail and telephone survey of health was administered in 1987 to VET Registry twins. PRINCIPAL FINDINGS: Variance component estimates under the best-fitting model included a 39.6 percent genetic contribution to self-reported health. In a model which included the effect of health condition, genes accounted for 32.5 percent and health condition accounted for 15.0 percent of the variance in self-reported health. The magnitude of the genetic contribution to perceived health status was not significantly different in a model with or without health condition. CONCLUSIONS: These data suggest over one-third of the variability of self-reported health can be attributed to genes. Since perceived health status is a major predictor of morbidity, mortality, and health services utilization, future analyses should consider the role of heritable influences on traditional health services variables.

Genetic and environmental influences on posttraumatic stress disorder, alcohol and drug dependence in twin pairs.

We investigated whether and to what degree genetic and environmental contributions overlap among posttraumatic stress disorder (PTSD), alcohol dependence (AD) and drug dependence (DD). Subjects were 3304 monozygotic and dizygotic male-male twin pair members of the Vietnam Era Twin Registry who participated in 1992 telephone administration of the Diagnostic Interview Schedule Version 3 Revised (DIS-3R). Genetic model fitting was performed to estimate the magnitude of genetic and environmental contributions to the lifetime co-occurrence of DSM-III-R PTSD, AD and DD. The liability for PTSD was partially due to a 15.3% genetic contribution common to AD and DD and 20.0% genetic contribution specific to PTSD. Risk for AD was partially due to a 55.7% genetic contribution common to PTSD and DD. Genetic influences common to PTSD and AD accounted for 25.2% of the total risk for DD. Specific family environmental influence accounted for 33.9% of the total variance in risk for DD. Remaining variance for all three disorders was due to unique environmental factors both common and specific to each phenotype. These results suggest that PTSD, AD and DD each have etiologically distinct components and also have significant genetic and unique environmental contributions in common.