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.

The classical twin design uses data on the variation of and covariation between monozygotic and dizygotic twins to infer underlying genetic and environmental causes of phenotypic variation in the population. By using data from additional relative classes, such as parents, extended twin family designs more comprehensively describe the causes of phenotypic variation. This article introduces an extension of previous extended twin family models, the Cascade model, which uses information on twins as well as their siblings, spouses, parents, and children to differentiate two genetic and six environmental sources of phenotypic variation. The Cascade also relaxes assumptions regarding mating and cultural transmission that existed in previous extended twin family designs. The estimation of additional parameters and relaxation of assumptions is potentially important, not only because it allows more fine-grained descriptions of the causes of phenotypic variation, but more importantly, because it can reduce the biases in parameter estimates that exist in earlier designs.