Genetic effects on the liability of developing pre-eclampsia and gestational hypertension

Genetic factors are known to be important in the etiology of pre-eclampsia and possibly also gestational hypertension, but the degree of genetic influence has not been quantified. To estimate the genetic and environmental effects on the liability of developing pre-eclampsia and gestational hypertension, we cross-linked the population-based Swedish Twin Register and the Swedish Medical Birth Register. We included female twin pairs with known zygosity, both of whom gave birth in Sweden from 1973 through 1993; in all 917 monozygotic and 1,199 dizygotic twin pairs. For pre-eclampsia, the estimates of heritability and nonshared environmental effect were 0. 54 (95% confidence interval 0-0.71) and 0.46 (0.29-0.67), respectively; corresponding estimates for gestational hypertension were 0.24 (0-0.53) and 0.76 (0.47-1.00), respectively. When considering both diseases as a single entity (pregnancy-induced hypertensive diseases), the heritability estimate was 0.47 (0.13-0. 61). These results suggest that genetic factors are important in the development of pre-eclampsia as well as gestational hypertension. The heritability estimates can be of importance when planning genetic linkage studies. In efforts to identify women with elevated risk of developing pre-eclampsia during pregnancy, a question about family history of pre-eclampsia should be included.     

Precision and Bias of a Normal Finite Mixture Distribution Model to Analyze Twin Data When Zygosity is Unknown: Simulations and Application to IQ Phenotypes on a Large Sample of Twin Pairs

The classification of twin pairs based on zygosity into monozygotic (MZ) or dizygotic (DZ) twins is the basis of most twin analyses. When zygosity information is unavailable, a normal finite mixture distribution (mixture distribution) model can be used to estimate components of variation for continuous traits. The main assumption of this model is that the observed phenotypes on a twin pair are bivariately normally distributed. Any deviation from normality, in particular kurtosis, could produce biased estimates. Using computer simulations and analyses of a wide range of phenotypes from the U.K. Twins’ Early Developments Study (TEDS), where zygosity is known, properties of the mixture distribution model were assessed. Simulation results showed that, if normality assumptions were satisfied and the sample size was large (e.g., 2,000 pairs), then the variance component estimates from the mixture distribution model were unbiased and the standard deviation of the difference between heritability estimates from known and unknown zygosity in the range of 0.02–0.20. Unexpectedly, the estimates of heritability of 10 variables from TEDS using the mixture distribution model were consistently larger than those from the conventional (known zygosity) model. This discrepancy was due to violation of the bivariate normality assumption. A leptokurtic distribution of pair difference was observed for all traits (except non-verbal ability scores of MZ twins), even when the univariate distribution of the trait was close to normality. From an independent sample of Australian twins, the heritability estimates for IQ variables were also larger for the mixture distribution model in six out of eight traits, consistent with the observed kurtosis of pair difference. While the known zygosity model is quite robust to the violation of the bivariate normality assumption, this novel finding of widespread kurtosis of the pair difference may suggest that this assumption for analysis of quantitative trait in twin studies may be incorrect and needs revisiting. A possible explanation of widespread kurtosis within zygosity groups is heterogeneity of variance, which could be caused by genetic or environmental factors. For the mixture distribution model, violation of the bivariate normality assumption will produce biased estimates.Edited by Dorret Boomsma     

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.     

Genetic effects on the liability of developing pre‐eclampsia and gestational hypertension

Genetic factors are known to be important in the etiology of pre‐eclampsia and possibly also gestational hypertension, but the degree of genetic influence has not been quantified. To estimate the genetic and environmental effects on the liability of developing pre‐eclampsia and gestational hypertension, we cross‐linked the population‐based Swedish Twin Register and the Swedish Medical Birth Register. We included female twin pairs with known zygosity, both of whom gave birth in Sweden from 1973 through 1993; in all 917 monozygotic and 1,199 dizygotic twin pairs. For pre‐eclampsia, the estimates of heritability and nonshared environmental effect were 0.54 (95% confidence interval 0–0.71) and 0.46 (0.29–0.67), respectively; corresponding estimates for gestational hypertension were 0.24 (0–0.53) and 0.76 (0.47–1.00), respectively. When considering both diseases as a single entity (pregnancy‐induced hypertensive diseases), the heritability estimate was 0.47 (0.13–0.61). These results suggest that genetic factors are important in the development of pre‐eclampsia as well as gestational hypertension. The heritability estimates can be of importance when planning genetic linkage studies. In efforts to identify women with elevated risk of developing pre‐eclampsia during pregnancy, a question about family history of pre‐eclampsia should be included. Am. J. Med. Genet. 91:256–260, 2000. © 2000 Wiley‐Liss, Inc.     

Twin analyses of chronic fatigue in a Swedish national sample

BACKGROUND: Chronic fatigue has infrequently been studied in twins. Data from twin studies can inform clinical and research approaches to the management and etiology of human complex traits. METHOD: The authors obtained telephone interview data on current chronic fatigue from 31406 individuals twins in the Swedish Twin Registry (aged 42-64 years, 75.68% response rate), from both members of 12407 pairs and from one member of 6592 pairs. Of the complete pairs, 3269 pairs were monozygotic, 9010 pairs dizygotic, and 128 pairs of unknown zygosity. Structural equation twin modeling was used to estimate the latent genetic architecture of varying definitions of fatiguing illness. RESULTS: Estimates of additive genetic effects, shared environmental effects, and individual-specific environmental effects were similar in males and females. No definition of current fatiguing illness (ranging from any fatigue to CFS-like illness) was strikingly distinctive. Individual-specific effects were the predominant source of variation, followed by modest genetic influences. We could not exclude a small but conceptually important contribution of shared environmental effects. CONCLUSIONS: Current fatiguing illness appears to be a complex trait resulting from both environmental and genetic sources of variation without pronounced differences by gender.     

Twin Pair Resemblance for Psychiatric Hospitalization in the Swedish Twin Registry: A 32-year Follow-up Study of 29,602 Twin Pairs

BACKGROUND: Allgulander et al. (Allgulander C, Nowak J, Rice JP (1991) Acta Psychiatr Scand 83, 12) published twin pair analyses of psychiatric hospitalization for like-sex pairs from the Swedish Twin Registry born 1926-1958. As noted in a subsequent letter (Allgulander C, Nowak J, Rice JP (1992) Acta Psychiatr Scand 86, 421), several features of the original study resulted in under-ascertainment of cases and underestimated heritability, particularly for alcoholism. The present report updates the prior results by using 17 additional years of follow-up, including members of opposite-sex twin pairs, and addressing biases arising from cohort effects and from excluding pairs with unknown zygosity. METHODS: Registry records for 29,602 twin pairs born 1926-1958 were matched against national databases of psychiatric and medical hospitalizations from 1972-2000 to obtain ICD diagnostic codes. Zygosity was known for 10,903 opposite-sex pairs and 15,401 like-sex pairs who participated previously in research. Twin-pair resemblance and genetic and environmental variance proportions were estimated for hospitalization for alcoholism, affective disorders, psychosis, and (in females) anxiety disorders. RESULTS: Hospitalization rates during the ascertainment window were: alcoholism: males = 3.67%, females = 0.94%; affective disorders: males = 1.99%, females = 2.75%; anxiety disorders: males = 0.46%, females = 0.74%; and psychotic disorders: males = 1.70%, females = 1.96%. Twins from like-sex pairs with unknown zygosity had significantly higher prevalences than those with known zygosity. Tetrachoric correlations and heritability estimates were affected by the method used to model unknown zygosity and cohort effects. CONCLUSIONS: Inclusion of additional follow-up information, opposite-sex twin pairs, age-adjustment, and use of current ICD definitions yielded higher heritability estimates for alcoholism, anxiety disorders, and psychosis than previously published for this nationally-representative sample of twins from Sweden. The results show that relatively small selection biases can alter twin study results and underscore the importance of addressing under-ascertainment of cases in genetic research based on volunteers.     

Twin method: Defense of a critical assumption

Since Galton's time, critics of the twin method have rejected the evidence of genetic differences in human behavior, because the twin method assumes that identical and fraternal pairs have equally similar environments. Twins whose genetic similarity is misperceived by themselves and others provide a critical test of the adequacy of this assumption. The relative effects of perceived and actual genetic similarity on cotwin differences in cognitive, personality, and physical development were assessed in a sample of young, adolescent twins whose genetic similarity was often misperceived. Twins' responses to questions about their own and other's judgments about their zygosity and physical similarity, and the ratings of similarity by eight judges, were used to estimate the perceived similarity of the twins. Actual zygosity was established by matching cotwins on 12 or more blood group loci. Perceived zygosity and perceived similarity by self and others were found to be insignificant biases in the twin study method.This research was supported by grants from the National Institute of Child Health and Human Development (HD-06502) and the W. T. Grant Foundation.     

Genetic and Environmental Influences on Age at Sexual Initiation in the Colorado Adoption Project

Whereas the majority of research on adolescent sexual initiation has focused solely on environmental factors, the present study used behavioral genetic analyses to investigate the relative contributions of genetic and environmental influences. Structural equation models were fitted to data from adoptive and non-adoptive sibling pairs (231 biologically related pairs and 169 unrelated pairs) from the Colorado Adoption Project. Information from censored individuals who had not yet experienced sexual initiation was maximized by adapting the twin survival analysis method of Pickles et al. (Behav Genet 24(5):457–468, 1994) to accommodate adoptive and non-adoptive siblings. Point estimates of variance components from an ACE model, including additive genetic (A), shared environmental (C), and non-shared environmental (E) influences were 28%, 24%, and 48%, respectively. Despite the lower point estimate for shared environmental effects than additive genetic effects, a CE model provided the best fit to the data. However, because adoptive siblings provide a direct estimate of shared environmental influences there is greater power to detect shared environmental effects in adoption designs. Evidence for genetic influences from our data were somewhat lower than those obtained in previous twin studies, possibly reflecting a return to more socially conservative sexual attitudes, changing sexual behaviors, or ambiguities in the wording of questions commonly used in research on adolescent sexuality.Edited by Richard Rose     

The Influence of Twin Pair Permutation on Likelihood-Based-Estimates of Genetic Variance That Require Ordering of Twin-Pairs

Results from analyses of twin data that use models assuming a bivariate distribution of twin values will change when twins within pairs are reordered. We examined the effect of twin pair ordering on additive genetic variance estimates and hypothesis tests, from a bivariate normal model, both via simulation and through examination of real twin data. The simulations generated twin data for varying sample sizes and amounts of additive genetic and common environmental variance. The real data sets had sample sizes of 60 or less per zygosity. The results indicate that for moderate or large size studies, the effects of twin pair ordering are unlikely to greatly change the results of the data analysis; but for small studies the results can be sensitive to twin pair ordering. We therefore suggest that methods, not sensitive to within twin-pair differences be compared to the results obtained from twin-pair ordering. Methods not influenced by twin-pair ordering include least squares methods or covariance matrices approaches as described by Carey (2005, Behav Genet 35:667–670) or Guo and Wang (2002, Behav Genet 32:37–49). Edited by Stacey Cherny     

Self-Reported Zygosity and the Equal-Environments Assumption for Psychiatric Disorders in the Vietnam Era Twin Registry

The equal-environments assumption (EEA) in twin studies of psychiatric disorders assumes that the family environment which contributes to risk for a disorder is equally correlated between monozygotic (MZ) and dizygotic (DZ) twin pairs. In a study of psychiatric disorders in female twins, Kendler and colleagues (1993) have demonstrated the utility of a test of the EEA which includes a specified family environmental factor defined by using measures of perceived zygosity. We tested the EEA assumption among 3155 male—male twin pair members of the Vietnam Era Twin Registry for the following DSM-III-R lifetime disorders: alcohol dependence, marijuana dependence, any illicit drug dependence, nicotine dependence, major depression, and posttraumatic stress disorder. The majority of MZ (81.6%; n = 1593) and DZ (90.2%; n = 1086) twin pairs agreed with the investigator's assigned zygosity. The best-fitting model for each of these disorders did not allow for a specified family environmental influence. These results support the usefulness of perceived zygosity in tests of the EEA. In male twin pairs, perceived zygosity has little impact on twin similarity for common psychiatric disorders.     

A test of the equal-environment assumption in twin studies of psychiatric illness

The traditional twin method is predicated on the equal-environment assumption (EEA)—that monozygotic (MZ) and dizygotic (DZ) twins are equally correlated in their exposure to environmental events of etiologic importance for the trait under study. In 1968, Scarr proposed a test of the EEA which examines the impact of phenotypic similarity in twins of perceived versus true zygosity. We apply this test for the EEA to five common psychiatric disorders (major depression, generalized anxiety disorder, phobia, bulimia, and alcoholism), as assessed by personal interview, in 1030 female-female twin pairs from the Virginia Twin Registry with known zygosity. We use a newly developed model-fitting approach which treats perceived zygosity as a form of specified familial environment. In 158 of the 1030 pairs (15.3%), one or both twins disagreed with the project-assigned zygosity. Model fitting provided no evidence for a significant influence of perceived zygosity on twin resemblance for any of the five disorders. Although limited in power, these results support the validity of the EEA in twin studies of psychiatric disorders.     

Additional Evidence Against Shared Environmental Contributions to Attention-Deficit/Hyperactivity Problems

A recent meta-analysis “Burt (Psychol Bull 135:608–637, 2009)” indicated that shared environmental influences (C) do not contribute to Attention-Deficit/Hyperactivity Disorder (ADHD). Unfortunately, the meta-analysis relied almost exclusively on classical twin studies. Although useful in many ways, some of the assumptions of the classical twin model (e.g., dominant genetic and shared environmental influences do not simultaneously influence the phenotype) can artifactually decrease estimates of C. There is thus a need to confirm that dominant genetic influences are not suppressing estimates of C on ADHD. The current study sought to do just this via the use of a nuclear twin family model, which allows researchers to simultaneously model and estimate dominant genetic and shared environmental influences. We examined two independent samples of child twins: 312 pairs from the Michigan State University Twin Registry and 854 pairs from the PrE School Twin Study in Sweden. Shared environmental influences were found to be statistically indistinguishable from zero and to account for less than 5 % of the variance. We conclude that the presence of dominant genetic influences does not account for the absence of C on ADHD.     

Predicting zygosity in Norwegian twin pairs born 1915–1960

Present addresses of 12,752 like-sexed twin pairs born in the period 1915-1960 were identified. A questionnaire, concerning the similarity of pair members, was sent to all individuals. Responses were obtained from 83.7% of the subjects. The zygosity of 207 pairs was established by examination of genetic markers. By using discriminant analysis on the responses from this subgroup, functions were obtained for prediction of zygosity from questionnaire data. It was estimated that 2.4% of the pairs would be misclassified if the questionnaire responses from both pair members were used, and 3.9% if only the response from one of the twins was used. Accordingly, zygosity could be predicted with satisfactory reliability also for twin pairs where only one of the twins had responded. The predicted percentage of monozygotic (MZ) pairs among pairs where one or both twins had responded, was 39.4 (4,402/11,175). The percentage of MZ pairs was significantly lower (34.5) in death-discordant pairs than in pairs in which both twins were alive (39.6). The zygosity questionnaire data are sufficient to adequately score twin pairs for zygosity in the great majority of cases.     

Multivariate genetic analyses of cognition and academic achievement from two population samples of 174,000 and 166,000 school children

The genetic influence on the association between contemporaneously measured intelligence and academic achievement in childhood was examined in nationally representative cohorts from England and The Netherlands using a whole population indirect twin design, including singleton data. We identified 1,056 same-sex (SS) and 495 opposite-sex (OS) twin pairs among 174,098 British 11?year-olds with test scores from 2004, and, 785 SS and 327 OS twin pairs among 120,995 Dutch schoolchildren, aged 8, 10 or 12?years, with assessments from 1994 to 2002. The estimate of intelligence heritability was large in both cohorts, consistent with previous studies (h (2)?=?0.70?±?0.14, England; h (2)?=?0.43?±?0.28-0.67?±?0.31, The Netherlands), as was the heritability of academic achievement variables (h (2)?=?0.51?±?0.16-0.81?±?0.16, England; h (2)?=?0.36?±?0.27-0.74?±?0.27, The Netherlands). Additive genetic covariance explained the large majority of the phenotypic correlations between intelligence and academic achievement scores in England, when standardised to a bivariate heritability (Biv h (2)?=?0.76?±?0.15-0.88?±?0.16), and less consistent but often large proportions of the phenotypic correlations in The Netherlands (Biv h (2)?=?0.33?±?0.52-1.00?±?0.43). In the British cohort both nonverbal and verbal reasoning showed very high additive genetic covariance with achievement scores (Biv h (2)?=?0.94-0.98; Biv h (2)?=?0.77-1.00 respectively). In The Netherlands, covariance estimates were consistent across age groups. The heritability of intelligence-academic achievement associations in two population cohorts of elementary schoolchildren, using a twin pair extraction method, is at the high end of estimates reported by studies of largely preselected twin samples.     

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 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.     

Testing the Equal Environments Assumption in the Children of Twins Design

In a Children of Twins (COT) design, the environmental and genetic risk of a child is, in part, dependent upon the status of the father and the father’s cotwin. The logic of the COT method breaks down if the zygosity of the twin pair is confounded with the environment provided to the child (a version of the Equal Environment Assumption, EEA). If MZ twin fathers see each other more often than DZ twin fathers, and a child’s uncle is the affected twin in discordant pairs, this could increase the environmental risk of children of MZ over that of DZ discordant twins. The current study was designed to test the EEA in the COT design, specifically in children of alcohol and drug dependent fathers. Results indicated that MZ twins did have more contact than DZ twins. Regression analyses were conducted to predict child externalizing symptom counts from father’s zygosity group status, level of contact with father’s cotwin, and their interaction. Results found no significant interaction between father’s zygosity and the higher level of cotwin contact (seen in MZ twins) in predicting several measures of offspring externalizing risk. The results of this study suggested that the COT design does not confound zygosity with differences in environmental risk exposure, findings that support the validity of the EEA within this research context.     

Genetic Innovation and Stability in Externalizing Problem Behavior Across Development: A Multi-Informant Twin Study

The use of cross-informant ratings in previous longitudinal studies on externalizing behavior may have obscured the presence of continuity of genetic risk. The current study included latent factors representing the latent estimates of externalizing behavior based on both parent and self-report which eliminated rater-specific effects from these latent estimates. Symptoms of externalizing behavior of 1,480 Swedish twin pairs were obtained at ages 8–9, 13–14, 16–17 and 19–20 both by parent and self-report. Mx modeling was used to estimate additive genetic, shared and specific environmental influences. Genetic continuity was found over the entire developmental period as well as additional sources of genetic influence emerging around early and late adolescence. New unique environmental effects (E) on externalizing behavior arose early in adolescence. The results support both the presence of genetic continuity and change in externalizing behavior during adolescence due to newly emerging genetic and environmental risk factors.     

Are Extended Twin Family Designs Worth the Trouble? A Comparison of the Bias,Precision, and Accuracy of Parameters Estimated in Four Twin Family Models

The classical twin design (CTD) uses observed covariances from monozygotic and dizygotic twin pairs to infer the relative magnitudes of genetic and environmental causes of phenotypic variation. Despite its wide use, it is well known that the CTD can produce biased estimates if its stringent assumptions are not met. By modeling observed covariances of twins’ relatives in addition to twins themselves, extended twin family designs (ETFDs) require less stringent assumptions, can estimate many more parameters of interest, and should produce less biased estimates than the CTD. However, ETFDs are more complicated to use and interpret, and by attempting to estimate a large number of parameters, the precision of parameter estimates may suffer. This paper is a formal investigation into a simple question: Is it worthwhile to use more complex models such as ETFDs in behavioral genetics? In particular, we compare the bias, precision, and accuracy of estimates from the CTD and three increasingly complex ETFDs. We find the CTD does a decent job of estimating broad sense heritability, but CTD estimates of shared environmental effects and the relative importance of additive versus non-additive genetic variance can be biased, sometimes wildly so. Increasingly complex ETFDs, on the other hand, are more accurate and less sensitive to assumptions than simpler models. We conclude that researchers interested in characterizing the environment or the makeup of genetic variation should use ETFDs when possible.