Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term ‘metabolomics’ refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.

Using information from Swedish population registries, we attempt to decompose the shared environment (C) into four subcomponents: close family, family, household, and community. Among pairs differing in their genetic and geographical/household relationships, we examine three externalizing syndromes: drug abuse (DA), criminal behavior (CB), and alcohol use disorders (AUD). The best-fitting common pathway model suggested that total estimates for C were higher for DA (21% for males and 18% for females) than for AUD (16% and 14%) and CB (17% and 10%). Concerning syndrome-specific influences in males, close family effects were stronger for CB and AUD, while community effects were stronger for DA. The two C components in between community experiences and close family experiences (family and household) were estimated to almost entirely derive from the common latent factor. In females, among the four components of C, the community experiences were just slightly above zero, while the C components referred to as the household effect were almost zero. The total close family experiences were similar and most important across syndromes were also divided into common and specific components. For all syndromes, for both males and females, the effects of additive genetic factors were 2–4 times the size of the total effect of the shared environment. Applying standard methods to novel relationships, we expand our understanding of how the shared environment contributes to individual differences in three externalizing syndromes.

Background: Shared experiences within families play an important role in the initiation of cigarette use among adolescents. Behavioral genetic studies using various samples have implicated that the shared environment that twins experience is an important source of influence on whether adolescents initiate cigarette use. Whether the special twin environment, in addition to the shared environment, contributes significantly to making twin siblings more similar in cigarette initiation, and whether the influence of the special twin environment persists into adulthood, is less clear. Methods: Data for this study came from the National Longitudinal Survey of Adolescent Health. Twin, full-, and half-sibling pairs between the ages of 12 and 33 were separated into three age groups, with about 3,000 individuals in each age group. The proportion of variance in cigarette use initiation explained by genetic, shared, special twin, and unique environmental factors were examined. Results: The results of separate age-moderated univariate variance decomposition models indicate that the special twin environment does not significantly contribute to the variance in cigarette use initiation in adolescence or young adulthood. Conclusion: Factors shared by individuals in a family, but that are not specific to being a twin, are important in determining whether adolescents will initiate the use of cigarettes.

The augmented multiple regression model for the analysis of data from selected twin pairs was extended to facilitate analyses of data from twin pairs and nontwin siblings. Fitting this extended model to data from both selected twin pairs and siblings yields direct estimates of heritability (h2) and the difference between environmental influences shared by members of twin pairs and those of sib or twin–sib pairs (i.e., c2(t) – c2 (s)). When this model was fitted to reading performance data from 293 monozygotic and 436 dizygotic pairs selected for reading difficulties, and 291 of their nontwin siblings, h2 = .48 ± .22, p = .03, and c2 (t) – c2 (s) = .22 ± .12, p = .06. Although the test for differential shared environmental influences is only marginally significant, the results of this analysis suggest that environmental influences on reading performance that are shared by members of twin pairs (.36) may be substantially greater than those for less contemporaneous twin–sibling pairs (.14).

In order to estimate the influence of genetic and environmental factors on ‘crying without a cause’ and ‘being easily upset’ in 2-year-old children, a large twin study was carried out. Prospective data were available for ~18,000 2-year-old twin pairs from the Netherlands Twin Register. A bivariate genetic analysis was performed using structural equation modeling in the Mx software package. The influence of maternal personality characteristics and demographic and lifestyle factors was tested to identify specific risk factors that may underlie the shared environment of twins. Furthermore, it was tested whether crying without a cause and being easily upset were predictive of later internalizing, externalizing and attention problems. Crying without a cause yielded a heritability estimate of 60% in boys and girls. For easily upset, the heritability was estimated at 43% in boys and 31% in girls. The variance explained by shared environment varied between 35% and 63%. The correlation between crying without a cause and easily upset (r = .36) was explained both by genetic and shared environmental factors. Birth cohort, gestational age, socioeconomic status, parental age, parental smoking behavior and alcohol use during pregnancy did not explain the shared environmental component. Neuroticism of the mother explained a small proportion of the additive genetic, but not of the shared environmental effects for easily upset. Crying without a cause and being easily upset at age 2 were predictive of internalizing, externalizing and attention problems at age 7, with effect sizes of .28–.42. A large influence of shared environmental factors on crying without a cause and easily upset was detected. Although these effects could be specific to these items, we could not explain them by personality characteristics of the mother or by demographic and lifestyle factors, and we recognize that these effects may reflect other maternal characteristics. A substantial influence of genetic factors was found for the two items, which are predictive of later behavioral problems.

Familial aggregation for disease is important; strong familial risk factors must exist even if the increased risk to a relative of an affected individual is modest. It is in practice difficult, however, to conduct studies in genetic epidemiology which conform to strict epidemiological principles. For twin studies there are two major questions: Are twins ‘no different’ from the population on which inference is to be made? Are study twins ‘no different’ to twins in the population? The importance of each question of bias depends on the scientific question, the trait(s) studied, and sampling issues. The strength of the twin design is its ability to refute the null hypothesis that genetic factors do not explain variation in a trait. Following the Popperian paradigm, alternate hypotheses should be considered in depth (both theoretically and empirically), with a design and sample size sufficient to exclude not just naive explanations. More sophisticated statistical techniques are now being applied, so the philosophy, assumptions, and limitations of statistical modelling must be appreciated. The concept of ‘heritability’ has, in the past, been misunderstood and misused. New advances in DNA technology promise to revolutionise epidemiological thinking, and so case-control-pedigree designs may well become standard tools. The strengths and limitations of studies based on related individuals as the sampling unit are discussed.