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.     

Toddler see,toddler do? Genetic and environmental influences on laboratory-assessed elicited imitation

The imitative performance of 311 pairs of 24-month old twins (143 MZ, 168 same-sex DZ) was assessed via three multi-step imitative sequences. Composite imitation score correlations suggested the presence of genetic influences on imitation, with MZ correlations significantly exceeding DZ correlations. Univariate model-fitting procedures supported this finding. Substantial broad heritability was found for imitative performance, with no evidence for shared environment. However, we are unable to say with certainty to what extent this heritability is represented by additive and nonadditive genetic variance. Estimates of heritability derived from both ACE and ADE model-fitting procedures accounted for approximately 50% of the total variance, with the remaining variance in imitative performance attributable to nonshared environmental factors. Edited by Dorret Boomsma & John K Hewitt     

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.     

Parent- and Observer-Rated Positive Affect in Early Childhood: Genetic Overlap and Environmental Specificity

The sources of individual differences in both observed and parent-rated positive affect (PA) were examined in a sample of 304 3-year-old twin pairs (140 MZ, 164 DZ). Based on model-fitting analyses, individual differences in observed PA were attributed to moderate genetic and high nonshared environmental factors, but not shared environmental factors. In contrast, shared environmental effects accounted for over half of the variance in parent-rated PA and genetic and nonshared environmental effects were more modest. The genetic correlation across the two measures was high, indicating substantial overlap between genetic factors influencing the two. It was these overlapping genetic effects that fully explained the phenotypic correlation between both measures. There was no significant covariance between the environmental influences on parent rated and observed PA. Thus, the two measures of PA in early childhood have common genetic underpinnings, whereas environmental influences are measure-specific. Measurement implications are discussed.     

Multiple raters of disruptive child behavior: Using a genetic strategy to examine shared views and bias

Most research on child behavior incorporates information from different individuals. While agreement between informants is generally only modest, there is little understanding of the processes underlying disagreement. In twin studies, differential agreement among raters for MZ and DZ twins is of particular concern. The processes underlying differences among mother, father, and child ratings of oppositional and conduct disorder symptoms are explored. Evidence in favor of a shared parental view of behavior is presented. Parental ratings give higher intrapair correlations, which could be due to either parents rating their twins more similarly or twins contrasting themselves. Rater bias and situational specificity are among the possible explanations of differential ratings. The effects of incorporating multiple raters of behavior on estimates of genetic and environmental effects are explored. These suggest that genetic influences are greater for the shared (multiple-rater) phenotype than for individual ratings; reduction in measurement error is only a partial explanation.     

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.     

The Implications of Simultaneous Smoking Initiation for Inferences about the Genetics of Smoking Behavior from Twin Data

We examined early social influences across stages of smoking within the context of a twin study using an environmental exposure specific to smoking: whether twins started smoking at the same time (“simultaneous smoking initiation”: SSI). We expected that SSI would be a good index of shared social influences on smoking initiation. Rates of SSI were indeed significantly higher in MZ twins and in twins who shared peers and classes, as well as in male twins. With the exception of regular smoking in females, we found no significant difference in estimates of genetic and environmental parameters between SSI and non-SSI pairs for any of the smoking measures that we examined (DSM-IV and Fagerstrom HSI measures of nicotine dependence; DSM-IV nicotine withdrawal; heavy smoking; and in males, regular smoking). For regular smoking in females, allowing for additional shared environmental influences associated with SSI only modestly reduced our estimates of additive genetic variance (56% vs. 68%). These results indicate the important social influences that may occur for smoking initiation do not appear to seriously bias estimates of genetic effects on later stages of smoking.     

Genetic effects on alcohol dependence risk: re-evaluating the importance of psychiatric and other heritable risk factors

BACKGROUND: Genetic influences have been shown to play a major role in determining the risk of alcohol dependence (AD) in both women and men; however, little attention has been directed to identifying the major sources of genetic variation in AD risk. METHOD: Diagnostic telephone interview data from young adult Australian twin pairs born between 1964 and 1971 were analyzed. Cox regression models were fitted to interview data from a total of 2708 complete twin pairs (690 MZ female, 485 MZ male, 500 DZ female, 384 DZ male, and 649 DZ female/male pairs). Structural equation models were fitted to determine the extent of residual genetic and environmental influences on AD risk while controlling for effects of sociodemographic and psychiatric predictors on risk. RESULTS: Risk of AD was increased in males, in Roman Catholics, in those reporting a history of major depression, social anxiety problems, and conduct disorder, or (in females only) a history of suicide attempt and childhood sexual abuse; but was decreased in those reporting Baptist, Methodist, or Orthodox religion, in those who reported weekly church attendance, and in university-educated males. After allowing for the effects of sociodemographic and psychiatric predictors, 47 % (95% CI 28-55) of the residual variance in alcoholism risk was attributable to additive genetic effects, 0% (95% CI 0-14) to shared environmental factors, and 53% (95% CI 45-63) to nonshared environmental influences. CONCLUSIONS: Controlling for other risk factors, substantial residual heritability of AD was observed, suggesting that psychiatric and other risk factors play a minor role in the inheritance of AD.     

A twin study of sex differences in social support

BACKGROUND: Social support may reduce the risk of psychiatric illness. Though perceived as an environmental measure, genetic factors may influence levels of social support. A relationship between social roles and personality with social support suggests possible sex effects on the sources of individual differences in social support. METHOD: We used the responses of MZ and DZ same and opposite sex twins to 16 questions regarding their social life. Six factors--friend support, relative support, friend problem, relative problem, confidants and social integration were used for structural equation modelling. Factor derived scales were analysed for genetic, shared and unique environmental influences. Quantitative and qualitative gender differences were analysed using the software package Mx. RESULTS: Except for relative support and confidants, no qualitative sex differences were seen. Genetic and individual specific environmental influences accounted for the variance for friend support, friend problems, relative problems and social integration and no quantitative gender differences were seen. For relative support genetic factors were detected in females but not males, while for confidants, the shared environment was important in females but not males. CONCLUSIONS: Except for relative support in males, genetic factors influence variation in all dimensions of social support. Shared environmental factors influence relative support and relative problems in both sexes. Sex differences were detected for confidants and relative support.     

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ～20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.     

Genetic and environmental influences on juvenile antisocial behaviour assessed on two occasions

BACKGROUND: There is conflicting evidence concerning the magnitude of genetic and shared environmental influences on juvenile antisocial behaviour (AB). The use of more than one assessment of AB may yield more accurate estimates of these influences. METHODS: Retrospective reports of antisocial behaviour prior to age 18 were obtained on two occasions from a population-based sample of 3522 adult males from male-male twin pairs: phone interviews (wave 1) and self-report questionnaires obtained 19 months later (wave 2). Structural equation modelling estimated the genetic and environmental influences on reliably-measured AB. Factors related to participation of co-twin at wave 1, attrition between waves 1 and 2, and reliability of wave 1 and wave 2 assessments were also investigated. RESULTS: Twin analyses revealed that genetic, shared environmental, and non-shared environmental influences accounted for approximately 33% (95% CI = 9-57%), 31% (95% CI = 10-51%) and 36% (95% CI = 29-44%) of the variance of reliably measured AB, respectively. We also found significant occasion-specific genetic influences on wave 1 AB. Wave 1 AB did not predict wave 1 participation of co-twin or attrition, but was related to reliability. Co-twins of MZ twins and younger twins were more likely to participate at wave 1; attrition was predicted by being a DZ twin, lack of initial participation of co-twin, fewer years of education, and fewer children. Being older, being unmarried, and having less psychopathology were associated with greater reliability. CONCLUSIONS: When measurement error is taken into account, both genetic and shared environmental factors are significant influences on juvenile AB, accounting for approximately one-third of variation. The origin of the specific genetic influences on wave 1 AB is unclear, but may be due to factors related to measurement.     

Genetic and environmental contributions to allergen sensitization in a Chinese twin study

Background Allergic disease is on the rise worldwide. Effective prevention of allergic disease requires comprehensive understanding of the factors that contribute to its intermediate phenotypes, such as sensitization to common allergens. Objective To estimate the degree of genetic and environmental contributions to sensitization to food and aeroallergens. Methods Sensitization was defined as a positive skin prick test to an allergen. We calculated the zygosity‐specific concordance rates and odds ratios (ORs) for sensitization to food and aeroallergens in 826 Chinese twin pairs [472 monozygotic (MZ) and 354 dizygotic (DZ)] aged 12–28 years. We also applied structural equation modelling procedures to estimate genetic and environmental influences on sensitization. Results The concordance rates and risk of sensitization in one twin given the presence vs. the absence of sensitization in the other twin were higher in MZ twins than those in DZ twins. However, a large number of MZ twins were discordant in sensitization to common allergens. These observations suggest both genetic and environmental factors influence sensitization. Consistently, the estimated heritability and individual environmental components of the liability to sensitization ranged from 0.51 to 0.68 and 0.32 to 0.49, respectively, based on the best‐fitted structural equation model. We also observed high phenotypic correlations between sensitization to two aeroallergens (cockroach and dust mite: 0.83) and two food allergens (peanut and shellfish: 0.58), but only moderate correlations for the pairs between sensitization to a food and an aeroallergen (0.31–0.46). The shared genetic and environmental factors between paired sensitizations contribute to the observed correlations. Conclusion We demonstrated that sensitization to common food and aeroallergens were influenced by both genetic and environmental factors. Moreover, we found that paired allergen sensitizations might share some common sets of genes and environmental factors. This study underscores the need to further delineate unique and/or pleiotropic genetic and environmental factors for allergen sensitization.     

A Twin Study of Drinking and Smoking Onset and Latencies from First Use to Regular Use

The early onset of alcohol and tobacco use has been associated with increased risk for later substance abuse and dependence problems. This study investigated genetic and environmental influences on age at onset of alcohol and tobacco use by examining twin resemblance for several retrospectively reported onset milestones including age at first use, age at first alcohol intoxication experience, and age at regular use. In addition, we also examined the latency between age at first use and age at regular use of tobacco and alcohol. The subjects were a volunteer sample of older adult twins 50 to 96 years of age. MZ twin correlations for age at first alcohol use and age at first tobacco use were .57 and .44, respectively, compared to .45 and .37 for DZ same-sex twins. MZ twins correlated .30 and .26 for the latencies between first use and regular use of alcohol and of tobacco, while DZ correlations were –.01 and .05, respectively. Biometrical model-fitting results confirmed that familial resemblance for age at first use for both alcohol and tobacco was largely the result of shared environmental factors, while the latencies between first use and regular patterns of use were more genetically influenced. These findings add to a growing body of literature suggesting that initiation of substance use is influenced primarily by environmental rather than genetic factors.     

Heritability of reproductive hormones in adult male twins

BACKGROUND: Proper functioning of the male reproductive axis depends on complex feedback systems between several hormones. In this study, the genetic contribution of various endocrine components of the hypothalamic-pituitary-testicular axis is evaluated and previously observed differences in FSH and inhibin B levels between mono- (MZ) and dizygotic (DZ) twins are re-investigated. METHODS: Inhibin B, FSH, LH, sex hormone-binding globulin (SHBG) and testosterone levels were assayed in 128 adult males (20 MZ twin pairs, 7 single MZ twins, 10 DZ twin pairs, 27 single DZ twins and 34 siblings of twins, constituting 10 sibling pairs), aged 15.6-68.7 years. Hormone levels were compared across zygosity groups and heritability estimates were obtained using maximum likelihood variance component analysis. RESULTS: Heritability estimates ranged from 56% (testosterone) to 81% (inhibin B and SHBG). For LH and FSH, the heritability was estimated at 68% and 80% respectively. No mean differences in hormone levels were observed across groups. CONCLUSIONS: All measured hormones are highly heritable. A difference in the FSH-inhibin B feedback system between DZ twin males and MZ twin males could not be confirmed.     

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.     

A genetic analysis of the Epworth Sleepiness Scale in 1560 World War II male veteran twins in the NAS-NRC Twin Registry

Responses to the eight-item Epworth Sleepiness Scale (ESS) obtained from 1560 World War II male veteran twin pairs [818 monozygotic (MZ), 742 dizygotic (DZ)] were analysed to determine the extent to which genetic influences are involved in self-reported daytime sleepiness in the elderly. Average ESS score (+/- SD) in this sample was 7.1 +/- 3.9, range 0--24. More than half of the twins (65%--67%) reported a moderate to high chance of falling asleep while lying down to rest; fewer than 3% admitted that this would occur while sitting and talking to someone or while stopped in traffic. Daytime sleepiness was not associated with age but was significantly and positively associated with obesity. The intraclass twin correlation on ESS scores was 0.39 in MZ pairs and 0.21 in DZ pairs (both P < 0.001). Structural equation modeling of the observed variance-covariance matrices for MZ and DZ twins estimated the heritability of ESS to be 38% (95% confidence interval 33%--44%). Environmental influences not shared by twin brothers accounted for the remaining variance in daytime sleepiness. A reasonable interpretation of the heritability of ESS in this healthy cohort of elderly male twins is a genetic susceptibility for disordered breathing during sleep.     

Habituation of the Skin Conductance Response to Strong Stimuli: A Twin Study

Skin conductance responses to a series of loud tones were measured bilaterally in 121 pairs of adult twins, 53 pairs reared together and 68 pairs reared apart. Subjects were given an absorbing task on which to focus their attention and instructed to ignore the meaningless tones. Rangecorrection eliminated hand and sex differences in SCR amplitude and also the correlation with age of this variable. For the combined group of 79 pairs of monozygotic (MZ) twins, the within-pair correlations for Y-intercept, the slope of the habituation curve, and the number of trials to habituation were near the limits of retest reliability for these variables. After range-correction, the correlation for Y-intercept for the 42 pairs of dizygotic (DZ) twins was about half the MZ value, suggesting that initial electrodermal reactivity is strongly genetic and can be interpreted according to a polygenic-additive model. Biometric model testing indicated that stable individual differences in uncorrected SCR amplitude and in habituation slope are primarily determined by non-additive genetic factors. About 40% of the total variance (and most of the stable variance) in number of trials to habituation is genetically determined. Co-twins of MZ twins who were electrodermal nonresponders tended also to be hyporesponsive while co-twins of DZ nonresponders tended to be normoresponsive.     

Genetic and Social Determinants of Initiation and Age at Onset of Smoking in Australian Twins

Retrospective data on age at onset of smoking, reported by 3810 adult Australian twin pairs, were analyzed to determine the role of genetic and environmental factors in the onset of smoking. Results of nonmetric multidimensional scaling supported a two-process model in which different etiologic factors determined which individuals were at risk of becoming smokers and the age at onset of smoking in those who were at risk. Parametric model-fitting confirmed this difference. For female twins and younger male twins (aged 30 years or less), the onset of smoking was strongly influenced by genetic factors, with shared and nonshared environmental effects having a more modest impact. For older male twins, shared environmental influences on onset of smoking were very important, and the influence of genetic predisposition was slight. The age at which smoking onset occurred, however, was influenced by both genetic and nonshared environmental effects, but not by shared environmental effects, in both sexes and both cohorts.     

Family Matters: Happiness in Nuclear Families and Twins

Biometric studies have shown that happiness is strongly affected by genes. The findings are mainly based on twin data, however, and the full validity of the results has been debated. To overcome some limitations in classical twin research, we examined aetiological sources of subjective well-being (SWB), using two independent population-based samples, one including nuclear families (N = 54,540) and one including twins (N = 6,620). Biometric modelling using R was conducted to test for a data structure implying either non-additive genetic effects or higher environmental co-twin correlation in MZ than DZ pairs (violation of the EEA). We also estimated non-random mating, cultural transmission and shared environments specific for regular siblings and twins. Two sets of nested models were fitted and compared. The best explanatory model shows that family matters for happiness predominantly due to quantitative sex-specific genetic effects, a moderate spousal correlation and a shared twin environment. Upper limits for broad-sense heritability were estimated to be 0.33 (females) and 0.36 (males). Our study constitutes the most elaborate biometric study of SWB to date and illustrates the utility of including responses from multiple types of relatives in quantitative genetic analyses.     

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.