A longitudinal twin study of skewed X chromosome-inactivation

X-chromosome inactivation (XCI) is a pivotal epigenetic mechanism involved in the dosage compensation of X-linked genes between males and females. In any given cell, the process of XCI in early female development is thought to be random across alleles and clonally maintained once established. Recent studies, however, suggest that XCI might not always be random and that skewed inactivation may become more prevalent with age. The factors influencing such XCI skewing and its changes over time are largely unknown. To elucidate the influence of stochastic, heritable and environmental factors in longitudinal changes in XCI, we examined X inactivation profiles in a sample of monozygotic (MZ) (n = 23) and dizygotic (DZ) (n = 22) female twin-pairs at ages 5 and 10 years. Compared to MZ twins who were highly concordant for allelic XCI ratios, DZ twins showed much lower levels of concordance. Whilst XCI patterns were moderately stable between ages 5 and 10 years, there was some drift over time with an increased prevalence of more extreme XCI skewing at age 10. To our knowledge, this study represents the earliest longitudinal assessment of skewed XCI patterns, and suggests that skewed XCI may already be established in early childhood. Our data also suggest a link between MZ twinning and the establishment of allelic XCI ratios, and demonstrate that acquired skewing in XCI after establishment is primarily mediated by stochastic mechanisms. These data have implications for our understanding about sex differences in complex disease, and the potential causes of phenotypic discordance between MZ female twins.     

A twin study of structural chromosome aberrations in lymphocytes

Structural chromosome aberrations were analyzed in peripheral lymphocytes of eight monozygotic (MZ) and seven dizygotic (DZ) pairs of male twins. There was no significant intrapair difference in the variance of aberration frequencies among the MZ and DZ twins. Thus, there was no evidence of a major genetic influence on the development of structural chromosome aberrations. Although a genetic component could not be excluded, it was concluded that any chromosome aberrations observed were probably due mainly to environmental influences.     

A twin study of genetic influences on epilepsy outcome.

The identification of genetic factors that confer susceptibility to the epilepsies has to date been the focus of genetic efforts in this field. Few studies have assessed the genetic contribution to disease course in epilepsy, yet an understanding of the genetic influences on epilepsy outcome is key to developing new therapeutic strategies. The aim of this study was to assess the genetic contributions to epilepsy outcome in twin pairs concordant for epilepsy. We studied 37 epilepsy concordant twin pairs (27 monozygotic, 10 dizygotic) in whom there were no recognized environmental contributions (e.g., acquired brain injury) to epilepsy, and in whom the most likely cause for epilepsy was a shared genetic susceptibility. Clinical outcome was determined using the binary measure of Seizure Status (seizure remission or recurrence) and on a six-category ordinal Outcome Scale. Epilepsy outcome was independent of age of seizure onset, age at assessment and major epilepsy syndrome diagnosis. The proportion of twin pairs concordant for Seizure Status was 0.81 (22/27) for monozygous and 1.0 (10/10) for dizygous pairs, p = 0.3. Within-pair correlation in outcome (Outcome Scale) was 0.60 (95% CI: 0.32, 0.78) in monozygous and 0.78 (0.48, 0.92) in dizygous pairs. These data provide no evidence for genetic influences on epilepsy outcome independent of those that contribute to disease susceptibility. The observed high correlations for outcome suggest that, for epilepsy, susceptibility genes also have a major influence on outcome.     

A high risk twin study of combat-related PTSD comorbidity.

Combat-related posttraumatic stress disorder (PTSD) is highly comorbid with other mental disorders. However, the nature of the relationship between PTSD and other mental disorders remains unclear. A discordant high-risk twin design was used on data from a sub-sample of the male-male twin pair members of the Vietnam Era Twin Registry to examine whether patterns of comorbidity are consistent with a psychopathological response to combat exposure or reflect familial vulnerability to psychopathology. Mental disorders were assessed via the Mental Health Diagnostic Interview Schedule Version III - Revised. Discordant monozygotic within-pair comparisons revealed that PTSD probands had higher symptom counts and diagnostic prevalences of mood and anxiety disorders than their non-combat exposed co-twins. Monozygotic co-twins of PTSD probands had significantly more mood disorder symptoms than monozygotic co-twins of combat controls or dizygotic co-twins of veterans with PTSD. These findings suggest that a) major depression, generalized anxiety disorder and panic disorder are part of a post-combat response syndrome; b) a shared familial vulnerability also contributes to the association between PTSD and major depression, PTSD and dysthymia, and c) this shared vulnerability is mediated by genetic factors.     

A twin titration microcalorimeter for the study of biochemical reactions

A small-volume (200 microliter) titration calorimeter of high sensitivity (1 mu cal ) has been developed for the purpose of studying biochemical reactions where the amounts of material are limited to a few nanomoles. High sensitivity is achieved by calorimetric twining , use of glass cells, elimination of vapor space, effective low-energy stirring, and reduction of measurement time. The calorimeter operates using the heat conduction principal with computer-controlled electrical compensation, which reduces the measurement time of each point from 10 to 3 min. This reduction in time is accompanied by a corresponding increase in the precision of measurement. The use of the calorimeter is demonstrated by a measurement of the heat of oxygenation of hemocyanin.     

A population-based twin study on sleep duration and body composition

The aim of this study is to investigate the relationship between sleep duration and body composition and to estimate the genetic contribution of sleep duration and body composition in a Chinese twin population. This cross-sectional analysis included 738 men and 511 women aged 21-72 year. Anthropometric and dual-energy X-ray absorptiometry (DXA) measures of body composition were used. Sleep duration was obtained from a standard sleep questionnaire. Multiple regression models were used to examine the association between sleep duration and body composition measures. Structural equation modeling was used to assess the heritability of sleep duration and body composition. Compared with individuals in the 2nd and 3rd age-specific quartiles of sleep duration (reference group), shorter (1st quartile) sleep duration among women but not men was associated with higher z-scores (0.248-0.317) for all adiposity measures--BMI, fat mass index (FMI), percent body fat mass (%BF), and percent trunk fat mass (%TF), P < 0.05 for each--and with 0.306 lower z-scores for percent body lean mass (%LM) and 0.353 lower lean/fat mass ratio (LFR), P < 0.01 for each. The heritability of sleep duration was 0.27 in men and 0.29 in women, while the heritability of body composition was as high as 0.56-0.73 after adjustment for age in both genders. Short sleep duration was associated with increased body fat and decreased lean body mass in women but not in men. Sleep duration was largely influenced by environmental factors while adiposity measures were mainly influenced by genetic factors.     

A population based twin study of sex differences in depressive symptoms.

Depressive symptoms reflect depressed mood over a relatively short period of time and are measured using symptom checklists such as the SCL-90. There is some evidence that depressive symptoms are associated with major depression (MD), which is a clinically diagnosed psychiatric illness. Genetic studies of depressive symptomatology suggest a role for genetic factors as well as unique environmental influences. While epidemiological research suggests that depressive symptoms may be influenced by sex-specific factors, few genetically informative findings support this result entirely. We used data from male and female same sex and opposite-sex twin pairs to assess the extent to which genetic, shared and unique environmental factors influence depressive symptoms. Furthermore, we tested for the presence of qualitative and quantitative sex differences in depressive symptoms. Our results suggest that similar to other studies, depressive symptomatology is moderately heritable (31%) with no evidence for shared environmental factors. Our best fitting model suggests that there are no qualitative or quantitative sex differences in depressive symptoms. Our analyses suggest that while there may be mean differences in the levels of depressive symptoms across sexes, the genetic and environmental factors that predispose males and females to depressive symptoms are not different.     

A twin study of dental dimension. II. Independent genetic determinants

To demonstrate the presence of independent genetic determinants of multiple correlated tooth dimensions from twin data, a multivariate analysis was performed on the covariance matrices of monozygotic and dizygotic within-pair differences for mesiodistal and buccolingual dimensions of 28 teeth of the secondary dentition. The results provided strong evidences that the correlation among tooth dimensions is primarily genetic in origin, probably attributable to the pleiotropic action of either independent genes or groups of genes. Among the genetic factors that were identified, one appeared to affect the maxillary teeth in general while a second influenced primarily the anterior mandibular teeth. There was a striking tendency for homologous measurements on the right and left sides to be associated with the same genetic factor. In contrast, genetic determination of the maxillary and mandibular dentition seemed to be independent of each other, and a wider range of genetic factors were found to influence the mandibular than the maxillary teeth, suggesting that a differential degree of evolutionary stability may have been achieved in the teeth of the two jaws.     

Genetic control of adrenergic receptors on human platelets. A twin study

It was examined whether genetic factors are involved in the expression of alpha-2 adrenergic receptors on human platelets, as measured with 3H-yohimbine as ligand. The twin series comprised 17 monozygotic and 15 dizygotic adult, healthy, male, drug-free twin pairs. For control of intraindividual and interassay variation, 13 unrelated pairs of subjects were examined. Bmax values for 3H-yohimbine binding (range 91-305 fmol/mg protein) proved to be under considerable genetic control; this was not the case for KD values. Different possible genetic mechanisms are discussed.     

A twin study of the etiology of prolonged fatigue and immune activation.

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors. Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwin-crosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation. By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49-0.69 versus 0.42-0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = -0.07 to -0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation. PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.     

Genetic basis of hair medulla by twin study

Data on the incidence of medulla of human head hair based on 9,600 strands examined from 48 pairs of zygosity — determined German twins were quantified as medullary ratio and subjected to variance analysis to give information about genetic significance of the character concerned. The results of F test and heritability estimate yielded significant values indicating the presence of a strong genetic component of variability in the incidence of medulla of human head hair. Sex influence upon the character is found to be absent.     

Cardiovascular reactions during psychiatric interview. A non-invasive study on a twin sample

A sample of 18 monozygotic and 13 dizygotic male twin pairs in the ages 51-74 (mean 62) was exposed to a stressful psychiatric interview. Genetic influence over blood pressure and peripheral pulse volume was observed to be most evident at the end of the interview, while heart rate was genetically strongly influenced both at rest and during the whole interview.     

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.     

A case-control study of vanishing twin as a risk factor for cerebral palsy.

It has been hypothesized that cerebral palsy of unknown etiology is the result of the death of an unrecognized co-twin--a vanishing twin--in early gestation. We conducted a case-control study of vanishing twin as a risk factor for cerebral palsy of unknown etiology in women who had an obstetric ultrasound during pregnancy. Among mothers of cases, one of 86 had evidence of a vanishing twin on ultrasound, as compared to two of 381 control mothers (odds ratio [OR] 2.2, 95% confidence interval [CI] 0.2-24.8; p = 0.5). Bleeding in early pregnancy, which may indicate the loss of a co-twin, was reported by 14 case mothers and 46 control mothers (OR 1.6, 95% CI 0.8-3.0; p = 0.3). On the basis of results presented here, the vanishing twin syndrome is unlikely to account for a high proportion of cases of cerebral palsy, but there is insufficient statistical power to draw firm conclusions.     

A Hungarian twin study on hand clasping, arm folding and tongue curling

A twin study was performed in adult Hungarian monozygotic and dizygotic pairs for hand clasping, arm folding and tongue curling. Genetic background of these traits could not be confirmed, although there appears to be a positive correlation between hand clasping type and handedness.     

A twin study of personality and illicit drug use and abuse/dependence.

Although personality measures such as neuroticism (N), extraversion (E) and novelty-seeking (NS) are associated with the use and abuse/dependence of illicit drugs, little is known about the degree to which these associations are due to genetic or environmental factors. The goal of this analysis was to estimate the extent of genetic and environmental overlap between three dimensions of personality (N, E and NS) and illicit psychoactive substance use and abuse/dependence. Using data from adult male and female twins from the Mid-Atlantic Twin Registry, we used the structural equation modeling package Mx to perform bivariate Cholesky decompositions for personality measures of N, E and NS, individually with cannabis, cocaine, sedatives, stimulants and hallucinogens. This was done separately for use and for a polychotomous diagnosis of abuse and/or dependence. Sex differences were tested. The phenotypic relationship between personality and use and abuse/dependence of illicit drugs were moderate and most of the covariance was explained by genetic factors. Sexes could be equated for N and E but not for NS. For NS, use and abuse/dependence of illicit drugs showed greater phenotypic and genetic overlap in males than females. Of the personality measures, NS and illicit drug use and abuse/dependence were most closely related. NS was most closely related to cannabis use while N showed significant genetic overlap with sedative use. NS in males appears to be a good indicator of risk for cannabis use. This result may be useful for candidate gene studies.