Cord blood immunoglobulin E in like-sexed monozygotic and dizygotic twins

Genetic and environmental factors have been implicated in the etiology of atopy and of serum IgE levels. In order to eliminate post-natal environmental influences we measured IgE in cord blood (CB-IgE) from a cohort of unselected, like-sexed twins. IgE determination was performed with a sensitive radioimmunoassay with a detection limit of 0.01 kU/l. Samples with contamination by maternal blood were identified by IgA determination and excluded. CB-IgE was evaluated in 29 monozygotic (MZ) and 28 dizygotic (DZ) twin pairs. The means and variances for IgE values were comparable for MZ and DZ twins when sex was controlled for. Placental anatomy (MZ twins with mono-and dichorial placenta and DZ twins with one or two placentae) had no significant influence on the IgE levels. In an analysis of variance with subsampling the among-pair, within-pair and analytical variance components were calculated. The analytical variance was well below the biological variances. Biometrical analysis showed that the best model by Akaike Information Criteria was a model including only additive genetic and non-shared environmental factors. With this model the heritability estimate was 0.8. These data suggest that the majority of the variation in CB-IgE is accounted for by genetic factors, but a substantial effect of a common environment cannot be excluded with the present sample size.     

The Impact of Variation in Twin Relatedness on Estimates of Heritability and Environmental Influences

By taking advantage of the natural variation in genetic relatedness among identical (monozygotic: MZ) and fraternal (dizygotic: DZ) twins, twin studies are able to estimate genetic and environmental contributions to complex human behaviors. Recently concerns have been raised about the accuracy of twin studies in light of findings of genetic and epigenetic changes in twins. One of the concerns raised is that MZ twins are not 100% genetically and epigenetically similar because they show variations in their genomes and epigenomes leading to inaccurate estimates of heritability. This article presents findings from a simulation study that examined the degree of bias in estimates of heritability and environmentality when the genetic and epigenetic similarity of MZ twins differs from 1.00 and when the genetic and epigenetic similarity of DZ twins differs from 0.50. The findings suggest that in the standard biometric model when MZ or DZ twin similarity differs from 1.00 or 0.50, respectively, the variance that should be attributed to genetic influences is instead attributed to nonshared environmental influences, thus deflating the estimates of genetic influences and inflating the estimates of nonshared environmental influences. Although estimates of genetic and nonshared environmental influences from the standard biometric model were found to deviate from “true” values, the bias was usually smaller than 10% points indicating that the interpretations of findings from previous twin studies are mostly correct.     

Genetic and Environmental Factors in Relative Body Weight and Human Adiposity

We review the literature on the familial resemblance of body mass index (BMI) and other adiposity measures and find strikingly convergent results for a variety of relationships. Results from twin studies suggest that genetic factors explain 50 to 90% of the variance in BMI. Family studies generally report estimates of parent–offspring and sibling correlations in agreement with heritabilities of 20 to 80%. Data from adoption studies are consistent with genetic factors accounting for 20 to 60% of the variation in BMI. Based on data from more than 25,000 twin pairs and 50,000 biological and adoptive family members, the weighted mean correlations are .74 for MZ twins, .32 for DZ twins, .25 for siblings, .19 for parent–offspring pairs, .06 for adoptive relatives, and .12 for spouses. Advantages and disadvantages of twin, family, and adoption studies are reviewed. Data from the Virginia 30,000, including twins and their parents, siblings, spouses, and children, were analyzed using a structural equation model (Stealth) which estimates additive and dominance genetic variance, cultural transmission, assortative mating, nonparental shared environment, and special twin and MZ twin environmental variance. Genetic factors explained 67% of the variance in males and females, of which half is due to dominance. A small proportion of the genetic variance was attributed to the consequences of assortative mating. The remainder of the variance is accounted for by unique environmental factors, of which 7% is correlated across twins. No evidence was found for a special MZ twin environment, thereby supporting the equal environment assumption. These results are consistent with other studies in suggesting that genetic factors play a significant role in the causes of individual differences in relative body weight and human adiposity.     

Partitioned twin analysis: A power study

Individual differences in the human genome may now be measured with molecular genetic techniques. Therefore, dizygotic (DZ) twins may be classified as sharing two, one, or zero genes identical by descent for any measured polymorphism. As a result, we may partition genetic variation into two sources: (i) genotypes at and closely linked to particular marker loci identified with restriction fragment length polymorphisms (RFLPs) and (ii) other genetic variation. The power of the classical twin study to reject false models lacking either a marker effect or a residual genetic effect is explored. Additivity of genetic effects at or near the locus and of the residual genetic variation as well as random environmental variation are assumed. Results indicate that statistical rejection of models could be achieved with sample sizes which are within the range of several current twin registers. A design including monozygotic (MZ) twins is compared with one consisting of only DZ twins. MZ twins add considerable power for the detection of residual genetic variation but provide no information to resolve genetic marker effects.This work was supported in part by NIH Grants HL 31010 and DK 39817, NATO Grant 86/0823, and grants from the Belgian National Research Fund, the state University of Gent, and the Catholic University of Leuven. We gratefully acknowledge the advice and encouragement of Drs. Lindon Eaves and Nicholas Martin.     

Influence of genetic variance on sodium sensitivity of blood pressure

Summary To examine the effect of genetic variance on blood pressure, sodium homeostasis, and its regulatory determinants, we studied 37 pairs of monozygotic twins and 18 pairs of dizygotic twins under conditions of volume expansion and contraction. We found that, in addition to blood pressure and body size, sodium excretion in response to provocative maneuvers, glomerular filtration rate, the renin-angiotensin system, and the sympathetic nervous system are influenced by genetic variance. To elucidate the interaction of genetic factors and an environmental influence, namely, salt intake, we restricted dietary sodium in 44 families of twin children. In addition to a modest decrease in blood pressure, we found heterogeneous responses in blood pressure indicative of sodium sensitivity and resistance which were normally distributed. Strong parent-offspring resemblances were found in baseline blood pressures which persisted when adjustments were made for age and weight. Further, mother-offspring resemblances were observed in the change in blood pressure with sodium restriction. We conclude that the control of sodium homeostasis is heritable and that the change in blood pressure with sodium restriction is familial as well. These data speak to the interaction between the genetic susceptibility to hypertension and environmental influences which may result in its expression.Abbreviations MZ monozygotic - DZ dizygotic - UNaV sodium excretion - FeNa fractional sodium excretion - UNeV norepinephrine excretion - PRA plasma renin activity - PA plasma aldosterone concentration - PNe plasma norepinephrine concentration - MABP mean arterial blood pressure Supported in part by grants from the USPHS, HL14159, HL27398, and RR00750, General Clinical Research Center     

Genetic and environmental influences on birthweight in a sample of Korean twins

This study is the first report of genetic and environmental influences on birthweight using Korean twins. The sample consisted of 255 monozygotic (MZ) and 178 dizygotic (DZ) twin pairs drawn from the Seoul Twin Family Study. Intraclass twin correlations were computed for the twins' birthweights obtained from parents (typically mothers) of the twins. To estimate genetic and shared and nonshared environmental influences on birthweight, standard univariate model-fitting analyses were performed using a software, Mx. For each gender, MZ twin correlations were higher than DZ twin correlations, suggesting existence of genetic influences on birthweight; however, DZ twin correlations were higher than half the MZ twin correlations, indicating that shared environmental factors are also important. For each zygosity, twin correlations were not significantly different between males and females, implicating that genes and environments that cause individual differences in birthweight may not vary between males and females. Model-fitting analyses based on the data pooled across gender yielded estimates of 17% for genetic, 60% for shared environmental, and 23% for nonshared environmental influences on birthweight.     

Causes of variation in birth weight: A study of offspring of twins

In an effort to explain the causes of variation in birth weight within and between families, birth weights of 13,970 sons and daughters of monozygotic (MZ) and dizygotic (DZ) twins were analysed. The sample included birth weights of halfsibs and cousins related either through females or males, permitting the distinction between maternal and fetal genetic effects. Models of genetic and environmental variances were fitted to mean squares from analysis of variance. The results indicate that more than 50% of the total variation in birth weight is caused by variation in fetal genes, and that less than 20% is caused by variation in maternal genes. The remaining variance (20–30%) could be explained by random environmental effects. No certain effects were found of family-specific environment or of interactions between fetal and maternal genes.     

Twin study of genetic and aging effects on X chromosome inactivation

To investigate the genetic influence on X chromosome inactivation and on age-related skewing of X inactivation, in particular, we analysed the X inactivation pattern (XIP) in peripheral blood cells from 118 young monozygotic (MZ) twin pairs (18-53 years), 82 elderly MZ twin pairs (55-94 years), 146 young dizygotic (DZ) twin pairs (20-54 years) and 112 elderly DZ twin pairs (64-95 years). Elderly twins had a higher frequency of skewed X inactivation (34%) than young twins (15%) (P<0.001). Our data suggest that the increase in skewing occurs after age 50-60 years. The intraclass correlation was 0.61 and 0.58 in young and elderly MZ twin pairs, and 0.08 and 0.09 in young and elderly DZ twin pairs. Biometric analysis showed that dominant genetic effects accounted for 63 and 58% of the variance of XIP in the young and elderly twin pairs, respectively. The dominant genetic effect and the shared environment for monochorionic MZ twins may explain the high intraclass correlation for the MZ twin pairs compared to the DZ twin pairs. We did not observe a significant decrease in the intraclass correlation in elderly MZ twins compared to young MZ twins, which would be expected if age-related skewing were due to stochastic factors. We conclude that the increased skewing with age implies that a genetically dependent selection of blood cells take place.     

Multivariate path analysis of cognitive ability measures in reading-disabled and control nuclear families and twins

Matrix notation is used to formulate a multivariate path model of familial resemblance in nuclear families, monozygotic (MZ) twin pairs, and dizygotic (DZ) twin pairs. The model incorporates multivariate genetic and environmental influences, cultural transmission, assortative mating, and environmental influences shared by offspring, and it permits the estimation of genetic and environmental correlations. The model is applied to data from nuclear families, MZ twin pairs, and DZ twin pairs in which at least one child was diagnosed as being reading disabled and to data from control families and twins. Three cognitive ability measures (Reading, Coding Speed, and Spatial Ability) were analyzed simultaneously. Results indicate that genetic influences are moderate, with significant genetic correlations among characters. Cultural transmission is negligible, as are the environmental correlations. Assortative mating is significant only for the Reading measure. There is no evidence for sibling shared environmental influences; however, there are significant twin shared environmental effects for each measure but not between measures.This work was supported by grants from the Spencer Foundation and the NICHD (HD-11681) to J. C. DeFries and by NIMH Postdoctoral Training Grant MH-17104.     

ADHD: sibling interaction or dominance: an evaluation of statistical power

Sibling interaction effects are suggested by a difference in phenotypic variance between mono-zygotic (MZ) twins and dizygotic (DZ) twins, and a pattern of twin correlations that is inconsistent with additive genetic influences. Notably, negative sibling interaction will result in MZ correlations which are more than twice as high as DZ correlations, a pattern also seen in the presence of genetic dominance. Negative sibling interaction effects have been reported in most genetic studies on Attention Deficit Hyperactivity Disorder (ADHD) and related phenotypes, while the presence of genetic dominance is not always considered in these studies. In the present paper the statistical power to detect both negative sibling interaction effects and genetic dominance is explored. Power calculations are presented for univariate models including sources of variation due to additive genetic influences, unique environmental influences, dominant genetic influences and a negative sibling interaction (i.e., contrast effect) between phenotypes of twins. Parameter values for heritability and contrast effects are chosen in accordance with published behavior genetic studies on ADHD and associated phenotypes. Results show that when both genetic dominance and contrast effects are truly present and using a classical twin design, genetic dominance is more likely to go undetected than the contrast effect. Failure to detect the presence of genetic dominance consequently gives rise to slightly biased estimates of additive genetic effects, unique environmental effects, and the contrast effect. Contrast effects are more easily detected in the absence of genetic dominance. If the significance of the contrast effect is evaluated while also including genetic dominance, small contrast effects are likely to go undetected, resulting in a relatively large bias in estimates of the other parameters. Alternative genetic designs, such as adding pairs of unrelated siblings reared together to a classical twin design, or adding non-twin siblings to twin pairs, greatly enhances the statistical power to detect contrast effects as well as the power to distinguish between genetic dominance and contrast effects.     

Widespread Evidence for Non-Additive Genetic Variation in Cloninger’s and Eysenck’s Personality Dimensions using a Twin Plus Sibling Design

Studies using the classical twin design often conclude that most genetic variation underlying personality is additive in nature. However, studies analyzing only twins are very limited in their ability to detect non-additive genetic variation and are unable to detect sources of variation unique to twins, which can mask non-additive genetic variation. The current study assessed 9672 MZ and DZ twin individuals and 3241 of their siblings to investigate the environmental and genetic architecture underlying eight dimensions of personality: four from Eysenck’s Personality Questionnaire and four from Cloninger’s Temperament and Character Inventory. Broad-sense heritability estimates from best-fitting models were two to three times greater than the narrow-sense heritability estimates for Harm Avoidance, Novelty Seeking, Reward Dependence, Persistence, Extraversion, and Neuroticism. This genetic non-additivity could be due to dominance, additive-by-additive epistasis, or to additive genetic effects combined with higher-order epistasis. Environmental effects unique to twins were detected for both Lie and Psychoticism but accounted for little overall variation. Our results illustrate the increased sensitivity afforded by extending the classical twin design to include siblings, and may provide clues to the evolutionary origins of genetic variation underlying personality.     

Statistical Power to Detect Genetic Loci Affecting Environmental Sensitivity

There is evidence in different species of genetic control of environmental variation, independent of scale effects. The statistical power to detect genetic control of environmental or phenotypic variability for a quantitative trait was investigated analytically using a monozygotic (MZ) twin difference design and a design using unrelated individuals. The model assumed multiplicative or additive effects of alleles on trait variance at a bi-allelic locus and an additive (regression) model for statistical analysis. If genetic control acts on phenotypic variance then the design using unrelated individuals is more efficient but 10,000s of observations are needed to detect loci explaining at most 3.5% of the variance of the variance at genome-wide significance. If genetic control acts purely on environmental variation then an MZ twin difference design is more efficient when the MZ trait correlation is larger than ~0.3. For a locus that explains a given proportion of the variation in variance, twice the number of observations is needed for detection when compared to a locus that explains the same proportion of variation in phenotypes.     

Genetic influence on the serum levels of naturally occurring human IgG antibodies to dietary antigens. Quantitative assessment from a twin study

Serum IgG antibodies to ovalbumin (OA) and beta-lactoglobulin (BLG) were quantified by ELISA techniques in 22 monozygotic (MZ) and 24 dizygotic (DZ) healthy twin pairs. Antibody levels were comparable in the MZ and DZ groups both for anti-OA and anti-BLG antibodies. The genetic variance (GWT) was 0.167 for log IgG anti-OA antibodies, and 0.173 for log IgG anti-BLG antibodies, with heritability estimates of 0.44 and 0.37, respectively. No indication was observed of genotype-environmental interaction or differential environmental covariance for the log antibody levels in the MZ and DZ twins. The anti-OA and anti-BLG antibody levels in the same individual correlated only to a low degree. The levels of naturally occurring serum IgG antibodies are significantly influenced by genetic factors.     

Birth weight and anthropometric measurements of twins

Background: Genetic and environmental influences on anthropometric measures can be investigated by comparing dizygotic (DZ) versus monozygotic (MZ) twins. Investigating cohorts living in different geographical areas across the globe can identify the variation in heritability versus environment.

Aims: (1) To investigate the association between birth weight and anthropometric measurements during adulthood; (2) to study the genetic and environmental influences on body measures including birth weight, weight and height among twins; and (3) to assess the variation in heritability versus environment among two cohorts of twins who lived in different geographical areas.

Subjects and methods: Twins were collected from two twin registers. Data on birth weight, adult weight and height in 430 MZ and 170?DZ twins living in two geographically distinct parts of the world were collected. A genetic analysis was performed using MX software.

Results: Birth weight was associated with weight, height and BMI. Both MZ and DZ twins with low birth weight had shorter height during their adult life (p?=?0.001), but only MZ twins with lower birth weight were lighter at adulthood (p?=?0.001). Intra-pair differences in birth weight were not associated with differences in adult height (p?=?0.366) or weight (p?=?0.796). Additive genetic effects accounted for 53% of the variance in weight, 43% in height and 55% in birth weight. The remaining variance was attributed to unique environmental effects (15% for weight, 13% for height and 45% for birth weight and only 16% for BMI). Variability was found to be different in the two cohorts. The best fitting model for birth weight and BMI was additive genetic and non-shared environment and for weight and height was additive genetic, non-shared environment (plus common Environment).

Conclusions: Data suggests that the association between weight at birth and anthropometric measures in later life is influenced by both genetic and environmental factors. Living in different environments can potentially relate to variation found in the environment.     

A twin analysis of dietary intake: Evidence for a need to control for possible environmental differences in MZ and DZ twins

In the NHLI Twin Study MZ twins are shown to get together substantially more often than DZ twins. With this result as an indicator of differences in shared environment, the assumption of equal shared environmental variation for MZ and DZ twins is assessed using nutritional data calculated from a food frequency questionnaire. Six nutrients show significant genetic variance for the total sample. However, when stratified on the basis of how frequently twins see each other, none of the nutrients shows significant genetic variance for both strata. A similar pattern is seen for several individual items from the questionnaire. In addition, four of the nutrients show significant correlation between the absolute difference in the nutrient intake of MZ twin pairs and how often they get together. These data appear to show that unequal environmental effects may lead to falsely high estimates of genetic variance for nutrient intake.     

Genetics and personality inventories: The limits of replication with twin data

The consistency of twin data with personality questionnaires is examined using all reported twin samples which have been administered the California Psychological Inventory. The scale correlations for the MZ twins are fairly consistent across different samples while the correlations for DZ twins fail to show as much consistency. Differences, moreover, between MZ and DZ correlations fail to replicate across samples. Sampling error and sampling bias are proposed as the major reasons for the inconsistency, and when these factors are taken into account the resulting heritabilities suggest that the CPI scales loading on the extraversion-introversion factor are the most heritable. The implications of sampling error and sampling bias for estimating genetic parameters from correlational twin data, for uncovering differential heritability of personality traits, and for designing future research are discussed.This work was supported in part by a Mental Health Training Grant in Biological Sciences (MH10679) awarded to Sheldon Reed and Irving I. Gottesman and by a grant from the University Computer Center of the University of Minnesota, Minneapolis.     

Environmental Factors in Obsessive-Compulsive Behavior: Evidence from Discordant and Concordant Monozygotic Twins

To investigate environmental factors that protect against or exacerbate obsessive-compulsive (OC) symptoms, we selected 25 monozygotic (MZ) twin pairs discordant, 17 MZ twin pairs concordant high and 34 MZ pairs concordant low on OC symptoms from a large longitudinal Dutch sample of adult twin pairs and their family members, applying stringent criteria for OC symptomatology. Data were collected on psychopathology, family structure, health, lifestyle, birth complications and life events. Unique environmental factors were studied using within-discordant MZ pair comparisons, whereas between-concordant MZ pair comparisons were used to study environmental factors that are shared by the twins of an MZ pair. The high-scoring MZ twins of the discordant group reported more life events (especially sexual abuse) than their low-scoring twin-siblings. The between-pair comparisons showed lower birth weight in the discordant MZ pairs than in the concordant MZ pairs. Further, the concordant high MZ pairs as well as their spouses had a lower educational level than the two other groups. On scale scores of anxious-depression, neuroticism, and somatic complaints, concordant high MZ pairs showed highest scores, and the discordant MZ pairs scored intermediate, except for neuroticism, on which the high-scoring twins of discordant MZ pairs were equal to the concordant high pairs. Discordance on psychological scale scores between the concordant MZ pairs was evident from 1991 onward, and within the discordant MZ pairs from 1997 onward, confirming previous reports of an association of early-onset OC symptoms with higher genetic load. Parent scores of OC symptoms and anxious-depression suggested intermediate genetic load in the discordant MZ group. In conclusion, this study reports on both unique and shared environmental factors associated with OC symptomatology. Whether these factors operate in addition to or in interaction with genetic disposition is to be elucidated in future studies. Edited by Tatiana Foroud.     

Twin-family studies of perceptual speed ability

Perceptual speed tests exhibit consistent sex differences, and an X-linked dominant gene has been hypothesized to explain female superiority in the aptitude. To evaluate that hypothesis, two tests from the ETS battery were administered to like-sex twins of college age, adult monozygotic twins, and their spouses and children. Offspring of MZ twins are genetic half-siblings reared as cousins in separate households; comparisons of the half-fraternities and half-sororities of male and female twin parents provide a direct test of X linkage. Test scores were transformed within age bands, and the age-sex standardized scores were evaluated for genetic variance and X-linked transmission. The analysis documents substantial heritability in perceptual speed that is inconsistent with X linkage. Gender differences in the ability may reflect polygenic transmission, with differing thresholds arising from cultural stereotypy in sex-role training.This is publication No. 78-42 from the Department of Medical Genetics and was supported by a USPHS Training Grant (GM 1056) and by the Indiana University Human Genetics Center (GM 21054).     

A source of variance in IQ unique to the lower-scoring monozygotic (MZ) cotwin

Environmental factors more common in twins than singletons appear to be disadvantageous with respect to intelligence. If these factors contribute to within-pair differences in IQ, the effect should be found more in the cotwin lower in IQ (the low twin) than in the cotwin higher in IQ (the high twin). In this case, the variance of the low twins should exceed that of the high twins. This hypothesis was tested for five samples of monozygotic (MZ) twins and three samples of dizygotic (DZ) twins but was confirmed only for the MZ samples. These results suggest that there are disadvantageous environmental factors unique to MZ twins which contribute to within-pair variability. Such factors will cause heritability coefficients obtained using MZ twins to be underestimated.