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The continuing value of twin studies in the omics era

Key Points

  • Twins are valuable subjects for studies in which control over genetic background and early environmental influences is desired.

  • Monozygotic twins are derived from a single zygote and are therefore matched for genetic background. Dizygotic twins are derived from two zygotes and share the same amount of genetic material as normal siblings. Both types of twins share prenatal and early environmental influences.

  • Twin registries worldwide have established vast collections of longitudinal phenotypic data as well as biological material in twins, offering a valuable resource for studying the molecular biology of complex traits.

  • The classical twin design compares the phenotypic similarity of monozygotic and dizygotic twins to estimate the importance of heritable and environmental influences on complex trait variation. Classical twin studies have provided estimates of heritability for numerous traits in the biomedical, psychiatric and behavioural domain.

  • Multivariate twin studies address the causes of association among phenotypes. Associations can be among different phenotypes or across age and are explained by common genetic or environmental influences.

  • We describe studies that applied the classical twin design to unravel the importance of genetic and environmental influences on variation in DNA methylation, gene expression, metabolomic and proteomic profiles in various tissues and on the composition of gut microbial communities.

  • The comparison of molecular profiles of phenotypically discordant monozygotic twin pairs is a powerful method to identify molecular characteristics associated with complex traits, including point mutations and genomic structural variation, differentially expressed and differentially methylated genes and metabolic profiles. Examples of this approach are given for a range of disorders and traits.

Abstract

The classical twin study has been a powerful heuristic in biomedical, psychiatric and behavioural research for decades. Twin registries worldwide have collected biological material and longitudinal phenotypic data on tens of thousands of twins, providing a valuable resource for studying complex phenotypes and their underlying biology. In this Review, we consider the continuing value of twin studies in the current era of molecular genetic studies. We conclude that classical twin methods combined with novel technologies represent a powerful approach towards identifying and understanding the molecular pathways that underlie complex traits.

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Figure 1: Liability threshold model and disease discordance in monozygotic twins.

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Acknowledgements

This work was supported by the European Research Council (ERC 230374) and the Institute for Health and Care Research (EMGO+).

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Correspondence to Dorret I. Boomsma.

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Supplementary information S1 (table)

Twin registries worldwide (PDF 181 kb)

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FURTHER INFORMATION

Dorret I. Boomsma's homepage

Australian Twin Registry

Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL)

Netherlands Consortium for Healthy Ageing

Queensland Twin Registry

Glossary

Classical twin design

The approach used to estimate the importance of genetic and environmental influences on complex trait variation. The estimate of heritability is based on a comparison of resemblence in monozygotic twins (who share all segregating genetic material) and dizygotic twins (who share, on average, half of their segregating genetic material).

Heritability

The proportion of variation in a trait that is due to heritable differences between individuals in a population: that is, the proportion of variation due to additive genetic effects (that is, narrow-sense heritability) or the proportion of variation due to all genetic effects (that is, broad-sense heritability).

Discordant monozygotic twins

(Discordant MZ twins). Twins who derive from a single fertilized egg cell but who are dissimilar for a certain characteristic or disease. By contrast, concordant MZ twins are phenotypically similar.

Case–control study

The comparison of individuals with a trait or disease of interest (cases) to controls to identify genes or other aspects associated with the trait. Cases and controls can be unrelated or can be relatives (within-family case–control design).

Epigenome

The entire collection of epigenetic marks, including DNA methylation and histone modifications, that regulate the expression of the genome. In contrast to the genome, the epigenome is specific to each cell.

Transcriptome

The total set of RNA transcripts that are produced in a cell or tissue by transcription of DNA.

Metabolome

The total set of small molecules (for example, lipids, amino acids and sugars) that are the reactants, intermediates or end products of cellular metabolism and that are present in a cell, tissue or complete organism.

Proteome

The entire complement of proteins that are present in a cell, tissue or complete organism.

Microbiome

The entire set of genomes of microorganisms (for example, bacteria, fungi and viruses) that are present in a certain environment: for example, in the human gut.

Variability genes

Genes that contribute to the variation in a phenotype. The genotypes are associated with phenotypic variance rather than with the mean level or frequency of the trait.

Zygosity assessment

The assessment whether same-sex twins are monozygotic or dizygotic is often based on the comparison of DNA markers or alternatively on standardized questionnaires.

Multivariate twin models

Models used for the simultaneous analysis of multiple traits measured in monozygotic and dizygotic twins to estimate the importance of genetic and environmental influences shared ('overlapping') between traits in explaining their clustering, comorbidity or covariance.

Genetic non-additivity

Refers to genetic effects that contribute to the phenotypic variance in a non-additive manner. These include the effects of interacting alleles at a single locus (dominance) and interactions between different loci (epistasis).

Assortative mating

Refers to the situation whereby a trait is correlated in spouses because it influences partner choice (phenotypic assortment) or because it correlates with certain environments that influence partner choice (social homogamy). It is also called nonrandom mating.

Maternal effects

Effects that are transmitted from mother to offspring, including genetic effects. The phenotype in offspring can be influenced by: the maternal allele, mitochondrial inheritance, the effects of the prenatal environment (for example, nutrient supply in utero) or the maternal supply of RNA or proteins to the egg cell.

Co-twin control method

A method of examining the associations between traits using discordant twins. If monozygotic twins who are discordant for trait 1 are also discordant for trait 2, the association between these traits is unlikely to be confounded by underlying shared genetic or early environmental influences.

Transgenerational inheritance

The transmission of a trait across generations (genetic or cultural inheritance). Epigenetic variation may also be transmitted across generations.

Imprinting

The mechanism that can occur at some loci to silence the expression of one of the two alleles, depending on the parent-of-origin of the allele.

Copy number variations

(CNVs). These refer to large DNA segments (> 1 kb) of which the number of copies is variable (for example, between individuals or between cells within an individual) — for example insertions, deletions and duplications.

Congenital diaphragmatic hernia

A birth defect that is characterized by malformation of the diaphragm, lung hypoplasia and pulmonary hypertension.

Oesophageal atresia

A congenital malformation of the oesophagus in which the oesophagus does not form an open passage to the stomach and may be connected to the trachea.

Maximum likelihood

Maximum-likelihood estimation obtains estimates of population parameters from a data set by computing the probability (likehood) of obtaining the observed data for a range of different parameter values and evaluating for which values the probability of observing the data is highest.

Dravet's syndrome

A childhood-onset epileptic encephalopathy that is also called severe myoclonic epilepsy of infancy.

Mosaicism

The situation in which the tissue of an individual consists of two or more genetically distinct cell lines owing to somatic mutation but originally derived from one (genetically homogeneous) zygote.

Non-coding RNAs

RNA transcripts that are not translated into protein but probably serve a regulatory function.

MicroRNAs

(miRNAs). A type of non-coding RNA with an average length of 22 nucleotides that has been suggested to have an important role in post-transcriptional gene regulation networks.

Lymphoblastoid cell lines

Cell lines derived from lymphocytes that have been immortalized, cultured and stored to provide a renewable source of DNA and RNA.

Interferon signalling

(IFN signalling). A signalling system for communication between cells that is involved in the immune response to pathogens and tumours.

Expression quantitative trait loci

(eQTLs). Genomic regions that are associated with the level of expression of an RNA transcript. eQTLs can be tissue-specific.

Mass spectrometry

A technique for determining the mass-to-charge ratio of ions on the basis of their separation in an electromagnetic field. The measured ratios and their relative intensities provide information about both the identity and the abundance of the molecules that gave rise to the ions.

1H NMR spectroscopy

A metabolomics technique that provides information about the structure and quantity of hydrogen-containing molecules. It is based on the absorption and emittance of radiofrequency energy by hydrogen atoms when placed in a strong magnetic field, with wavelengths depending on the atoms' position in the molecule.

Lipid bilayer dynamics

The dynamic properties of lipid bilayer membranes, such as thickness, fluidity and permeability, that influence the physiological properties of a cell.

Lipidomics

The comprehensive study of the entire set of lipids in biological systems, such as cells, tissues and organs, using metabolomics techniques.

Chimerism

The situation in which an individual carries some of the genetic material originating from another individual (for example, originating from the co-twin or originating from the mother).

Microbiota

The collection of all microorganisms living in a certain environment (for example, the human gut).

Identity-by-descent sharing

(IBD sharing). Refers to the proportion of alleles in two individuals that are derived identically by descent from a common ancestor.

Monochorionic

Describes twins who share the outer membrane (chorion) surrounding the embryos in utero. Monochorionic monozygotic twins result when the zygote splits ≥3 days after fertilization.

Dichorionic

Describes twins who do not share the chorion surrounding the embryos in utero. Dizygotic twins are always dichorionic. Dichorionic monozygotic twins result when the zygote splits early after fertilization.

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van Dongen, J., Slagboom, P., Draisma, H. et al. The continuing value of twin studies in the omics era. Nat Rev Genet 13, 640–653 (2012). https://doi.org/10.1038/nrg3243

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