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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Schizophrenia Open Access 02 March 2022
Behavior Genetics Open Access 01 February 2021
Scientific Reports Open Access 01 September 2020
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Javierre, B. M. et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 20, 170–179 (2010).
McRae, A. F. et al. Replicated effects of sex and genotype on gene expression in human lymphoblastoid cell lines. Hum. Mol. Genet. 16, 364–373 (2007).
York, T. P. et al. Epistatic and environmental control of genome-wide gene expression. Twin Res. Hum. Genet. 8, 5–15 (2005).
Martin, N. G. & Eaves, L. J. The genetical analysis of covariance structure. Heredity 38, 79–95 (1977).
Kendler, K. S., Heath, A. C., Martin, N. G. & Eaves, L. J. Symptoms of anxiety and symptoms of depression: same genes, different environments? Arch. Gen. Psychiatry 44, 451–457 (1987). This paper describes one of the first studies that used data from MZ and DZ twins to assess whether the co-occurrence of psychiatric symptoms is explained by a shared genetic or environmental aetiology.
Middeldorp, C. M., Cath, D. C., Van Dyck, R. & Boomsma, D. I. The co-morbidity of anxiety and depression in the perspective of genetic epidemiology. A review of twin and family studies. Psychol. Med. 35, 611–624 (2005).
Brant, A. M. et al. The developmental etiology of high IQ. Behav. Genet. 39, 393–405 (2009).
Haworth, C. M. et al. The heritability of general cognitive ability increases linearly from childhood to young adulthood. Mol. Psychiatry 15, 1112–1120 (2010). This paper describes a study based on a large sample of twins from six twin cohorts, showing that the heritability of general cognitive ability increases significantly from childhood to young adulthood.
Purcell, S. Variance components models for gene-environment interaction in twin analysis. Twin Res. 5, 554–571 (2002). This paper describes the implementation of G×E interaction tests in variance component twin analysis, by modelling (unmeasured) genetic effects as a linear function of one or more measures of the environment or moderators.
Mustelin, L., Silventoinen, K., Pietiläinen, K., Rissanen, A. & Kaprio, J. Physical activity reduces the influence of genetic effects on BMI and waist circumference: a study in young adult twins. Int. J. Obes. 33, 29–36 (2008).
Posthuma, D. & Boomsma, D. I. A note on the statistical power in extended twin designs. Behav. Genet. 30, 147–158 (2000).
Eaves, L. J. Inferring the causes of human variation. J. R. Stat. Soc. Ser. A 140, 324–355 (1977).
Reynolds, C. A., Baker, L. A. & Pedersen, N. L. Models of spouse similarity: applications to fluid ability measured in twins and their spouses. Behav. Genet. 26, 73–88 (1996).
van Grootheest, D. S., van den Berg, S. M., Cath, D. C., Willemsen, G. & Boomsma, D. I. Marital resemblance for obsessive-compulsive, anxious and depressive symptoms in a population-based sample. Psychol. Med. 38, 1731–1740 (2008).
Magnus, P., Berg, K. & Bjerkedal, T. No significant difference in birth weight for offspring of birth weight discordant monozygotic female twins. Early Hum. Dev. 12, 55–59 (1985).
Nance, W. E., Kramer, A. A., Corey, L. A., Winter, P. M. & Eaves, L. J. A causal analysis of birth weight in the offspring of monozygotic twins. Am. J. Hum. Genet. 35, 1211–1223 (1983).
Vrieze, S. I. et al. An assessment of the individual and collective effects of variants on height using twins and a developmentally informative study design. PLoS Genet. 7, e1002413 (2011).
Maher, B. Personal genomes: the case of the missing heritability. Nature 456, 18–21 (2008).
Visscher, P. M., Brown, M. A., McCarthy, M. I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012).
Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nature Genet. 42, 565–569 (2010).
Zuk, O., Hechter, E., Sunyaev, S. R. & Lander, E. S. The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl Acad. Sci. USA 109, 1193–1198 (2012).
Friberg, L., Cederlof, R., Lundman, T. & Olsson, H. Mortality in smoking discordant monozygotic and dizygotic twins. A study on the Swedish Twin Registry. Arch. Environ. Health 21, 508–513 (1970).
Martin, N. G., Carr, A. B., Oakeshott, J. G. & Clark, P. Co-twin control studies: vitamin C and the common cold. Prog. Clin. Biol. Res. 103, 365–373 (1982).
de Moor, M. H., Boomsma, D. I., Stubbe, J. H., Willemsen, G. & de Geus, E. J. Testing causality in the association between regular exercise and symptoms of anxiety and depression. Arch. Gen. Psychiatry 65, 897–905 (2008).
Ligthart, L., Nyholt, D. R., Penninx, B. W. & Boomsma, D. I. The shared genetics of migraine and anxious depression. Headache 50, 1549–1560 (2010).
Lundqvist, E. et al. Co-twin control and cohort analyses of body mass index and height in relation to breast, prostate, ovarian, corpus uteri, colon and rectal cancer among Swedish and Finnish twins. Int. J. Cancer 121, 810–818 (2007).
Bell, J. T. & Spector, T. D. A twin approach to unraveling epigenetics. Trends Genet. 27, 116–125 (2011).
Fraga, M. F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl Acad. Sci. USA 102, 10604–10609 (2005). This is the first study indicating that epigenetic profiles of older MZ twins are less similar than those of young MZ twins based on a comparison of global and locus-specific DNA methylation and histone acetylation.
Talens, R. P. et al. Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell 23 May 2012 (doi:10.1111/j.1474-9726.2012.00835.x).
Wong, C. C. et al. A longitudinal study of epigenetic variation in twins. Epigenetics 5, 516–526 (2010).
Gordon, L. et al. Expression discordance of monozygotic twins at birth: effect of intrauterine environment and a possible mechanism for fetal programming. Epigenetics 6, 579–592 (2011).
Ollikainen, M. et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum. Mol. Genet. 19, 4176–4188 (2010).
Powell, J. E. et al. Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent. Genome Res. 22, 456–466 (2012).
Hjelmborg, J. B. et al. Genetic influence on human lifespan and longevity. Hum. Genet. 119, 312–321 (2006). This paper describes a study of survival in a large sample of twins, showing that genetic influences on human lifespan are of little importance until the age of 60 but that genes explain an important part of the variation at advanced ages.
Bakaysa, S. L. et al. Telomere length predicts survival independent of genetic influences. Aging Cell 6, 769–774 (2007).
Zwijnenburg, P. J. G., Meijers Heijboer, H. & Boomsma, D. I. Identical but not the same: the value of discordant monozygotic twins in genetic research. Am. J. Med. Genet. B 153, 1134–1149 (2010). This review provides an overview of studies of MZ twins who are discordant for chromosomal abnormalities, Mendelian disorders and other genetic disorders.
Forsberg, L. A. et al. Age-related somatic structural changes in the nuclear genome of human blood cells. Am. J. Hum. Genet. 90, 217–228 (2012).
Ehli, E. A. et al. De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on attention problems. Eur. J. Hum. Genet. 11 Apr 2012 (doi: 10.1038/ejhg.2012.49).
Veenma, D. et al. Copy number detection in discordant monozygotic twins of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA) cohorts. Eur. J. Hum. Genet. 20, 298–304 (2012).
Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nature Rev. Genet. 12, 363–376 (2011).
Baranzini, S. E. et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464, 1351–1356 (2010). This paper describes a study of female MZ twins who are discordant for multiple sclerosis, and it was the first to report the individual genome sequences of an MZ twin pair based on whole-genome sequencing technology.
Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nature Rev. Genet. 13, 565–575 (2012).
Vadlamudi, L. et al. Timing of de novo mutagenesis: a twin study of sodium-channel mutations. N. Engl. J. Med. 363, 1335–1340 (2010). This paper describes a study that sequenced SCN1A in multiple cell lines from MZ twin pairs who are concordant and discordant for Dravet's syndrome to obtain insight into the timing of disease-causing de novo mutations.
Oates, N. A. et al. Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am. J. Hum. Genet. 79, 155–162 (2006).
Mastroeni, D., McKee, A., Grover, A., Rogers, J. & Coleman, P. D. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease. PLoS ONE 4, e6617 (2009).
Nguyen, A., Rauch, T. A., Pfeifer, G. P. & Hu, V. W. Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J. 24, 3036–3051 (2010).
Kuratomi, G. et al. Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol. Psychiatry 13, 429–441 (2008).
Rosa, A. et al. Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am. J. Med. Genet. B 147, 459–462 (2008).
Gao, Y. et al. Increased expression and altered methylation of HERVWE1 in the human placentas of smaller fetuses from monozygotic, dichorionic, discordant twins. PLoS ONE 7, e33503 (2012).
Galetzka, D. et al. Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer. Epigenetics 7, 47–54 (2012).
Gervin, K. et al. DNA methylation and gene expression changes in monozygotic twins discordant for psoriasis: identification of epigenetically dysregulated genes. PLoS Genet. 8, e1002454 (2012).
Heijmans, B. T., Kremer, D., Tobi, E. W., Boomsma, D. I. & Slagboom, P. E. Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum. Mol. Genet. 16, 547–554 (2007).
Coolen, M. W. et al. Impact of the genome on the epigenome is manifested in DNA methylation patterns of imprinted regions in monozygotic and dizygotic twins. PLoS ONE 6, e25590 (2011).
Gertz, J. et al. Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet. 7, e1002228 (2011).
Kaminsky, Z. A. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nature Genet. 41, 240–245 (2009).
Amaral, P. P., Dinger, M. E., Mercer, T. R. & Mattick, J. S. The eukaryotic genome as an RNA machine. Science 319, 1787–1789 (2008).
Kim, V. N. MicroRNA biogenesis: coordinated cropping and dicing. Nature Rev. Mol. Cell. Biol. 6, 376–385 (2005).
Mattick, J. S. & Makunin, I. V. Non-coding RNA. Hum. Mol. Genet. 15 (Suppl. 1), R17–R29 (2006).
Sarachana, T., Zhou, R., Chen, G., Manji, H. K. & Hu, V. W. Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome Med. 2, 23 (2010).
Te, J. L. et al. Identification of unique microRNA signature associated with lupus nephritis. PLoS ONE 5, e10344 (2010).
Tan, Q. et al. Genetic dissection of gene expression observed in whole blood samples of elderly Danish twins. Hum. Genet. 117, 267–274 (2005).
Nica, A. C. et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 7, e1002003 (2011).
Pietiläinen, K. H. et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. 5, e51 (2008).
Haas, C. S. et al. Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins. Arthritis Rheum. 54, 2047–2060 (2006).
Matigian, N. et al. Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway. Mol. Psychiatry 12, 815–825 (2007).
Kakiuchi, C. et al. Upregulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147, 557–564 (2008).
Beyan, H. et al. Monocyte gene-expression profiles associated with childhood-onset type 1 diabetes and disease risk: a study of identical twins. Diabetes 59, 1751–1755 (2010).
Caramori, M. L. et al. Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes. Diabetes 61, 739–744 (2012).
Ronkainen, P. H. et al. Postmenopausal hormone replacement therapy modifies skeletal muscle composition and function: a study with monozygotic twin pairs. J. Appl. Physiol. 107, 25–33 (2009).
Ellis, D. I., Dunn, W. B., Griffin, J. L., Allwood, J. W. & Goodacre, R. Metabolic fingerprinting as a diagnostic tool. Pharmacogenomics 8, 1243–1266 (2007).
Nicholson, G. et al. Human metabolic profiles are stably controlled by genetic and environmental variation. Mol. Syst. Biol. 7, 525 (2011).
Kettunen, J. et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genet. 44, 269–276 (2012). This was a genome-wide association study of 216 serum metabolites that used twin data to compare the total heritability of each metabolite to the total genetic variance explained by significantly associated SNPs.
Nicholson, G. et al. A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection. PLoS Genet. 7, e1002270 (2011).
Pietiläinen, K. H. et al. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects — a monozygotic twin study. PLoS ONE 2, e218 (2007).
Pietiläinen, K. H. et al. Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans. PLoS Biol. 9, e1000623 (2011). This paper describes a simulation of adipocyte membrane dynamics related to obesity, based on differences in lipid content and differential gene expression detected in discordant monozygotic twins.
Kato, B. S. et al. Variance decomposition of protein profiles from antibody arrays using a longitudinal twin model. Proteome Sci. 9, 73 (2011).
Dempster, E. L. et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum. Mol. Genet. 20, 4786–4796 (2011).
van Dijk, B. A., Boomsma, D. I. & de Man, A. J. Blood group chimerism in human multiple births is not rare. Am. J. Med. Genet. 61, 264–268 (1996).
Laborie, L. B. et al. DNA hypomethylation, transient neonatal diabetes, and prune belly sequence in one of two identical twins. Eur. J. Pediatr. 169, 207–213 (2010).
Erlich, Y. Blood ties: chimerism can mask twin discordance in high-throughput sequencing. Twin Res. Hum. Genet. 14, 137–143 (2011).
Scheet, P. et al. Twins, tissue and time: a comparison of genomic structures. Twin Res. Hum. Genet. (in the press).
Spor, A., Koren, O. & Ley, R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nature Rev. Microbiol. 9, 279–290 (2011).
Stewart, J. A., Chadwick, V. S. & Murray, A. Investigations into the influence of host genetics on the predominant eubacteria in the faecal microflora of children. J. Med. Microbiol. 54, 1239–1242 (2005).
Zoetendal, E. G., Akkermans, A. D. L., Akkermans-van Vliet, W. M., de Visser, J. A. G. M. & de Vos, W. M. The host genotype affects the bacterial community in the human gastronintestinal tract. Microb. Ecol. Health Dis. 13, 129–134 (2001).
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2008). This paper describes a comparison of faecal microbial communities in monozygotic and dizygotic twins who are concordant for leanness or obesity.
Willing, B. P. et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139, 1844–1854 (2010).
Lepage, P. et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141, 227–236 (2011).
Kendler, K. S. & Eaves, L. J. Models for the joint effect of genotype and environment on liability to psychiatric illness. Am. J. Psychiatry 143, 279–289 (1986).
Stubbe, J. H. et al. Genetic influences on exercise participation in 37.051 twin pairs from seven countries. PLoS ONE 1, e22 (2006).
Teucher, B. et al. Dietary patterns and heritability of food choice in a UK female twin cohort. Twin Res. Hum. Genet. 10, 734–748 (2007).
Middeldorp, C. M., Cath, D. C., Vink, J. M. & Boomsma, D. I. Twin and genetic effects on life events. Twin Res. Hum. Genet. 8, 224–231 (2005).
Kendler, K. S. & Baker, J. H. Genetic influences on measures of the environment: a systematic review. Psychol. Med. 37, 615–626 (2007).
Vinkhuyzen, A. A. E., Van Der Sluis, S., De Geus, E. J. C., Boomsma, D. I. & Posthuma, D. Genetic influences on 'environmental' factors. Genes Brain Behav. 9, 276–287 (2010).
Caspi, A. & Moffitt, T. E. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nature Rev. Neurosci. 7, 583–590 (2006).
Caspi, A. et al. Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proc. Natl Acad. Sci. USA 104, 18860–18865 (2007).
Berg, K. Variability gene effect on cholesterol at the Kidd blood group locus. Clin. Genet. 33, 102–107 (1988).
Wray, N. R. et al. Use of monozygotic twins to investigate the relationship between 5HTTLPR genotype, depression and stressful life events: an application of item response theory. Novartis Found. Symp. 293, 48–59 (2008).
Visscher, P. M., Hill, W. G. & Wray, N. R. Heritability in the genomics era: concepts and misconceptions. Nature Rev. Genet. 9, 255–266 (2008).
Visscher, P. M. et al. Genome partitioning of genetic variation for height from 11,214 sibling pairs. Am. J. Med. Genet. 81, 1104–1110 (2007).
Jörgensen, G. in Erbgefüge (ed. Vogel, F.) 581–665 (Springer, 1974).
Smith, C. Heritability of liability and concordance in monozygous twins. Ann. Hum. Genet. 34, 85–91 (1970).
Tazi, L. et al. HIV-1 infected monozygotic twins: a tale of two outcomes. BMC Evol. Biol. 11, 62 (2011).
Ott, J., Kamatani, Y. & Lathrop, M. Family-based designs for genome-wide association studies. Nature Rev. Genet. 12, 465–474 (2011).
Galton, F. The history of twins, as a criterion of the relative powers of nature and nurture. J. Anthropol. Institute Great Britain Ireland 5, 391–406 (1876).
Mayo, O. Early research on human genetics using the twin method: who really invented the method? Twin Res. Hum. Genet. 12, 237–245 (2009).
Siemens, H. W. Die Zwillingspathologie. Mol. Gen. Genet. 35, 311–312 (1924).
Zhu, G. et al. A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions. Eur. J. Hum. Genet. 15, 94–102 (2007).
Jinks, J. L. & Fulker, D. W. Comparison of the biometrical genetical, MAVA, and classical approaches to the analysis of the human behavior. Psychol. Bull. 73, 311–349 (1970). This is a classical paper that describes the application of the biometrical genetic approach initiated by R. A. Fisher to the analysis of twin and family data.
Martin, N. G., Eaves, L. J., Kearsey, M. J. & Davies, P. The power of the classical twin study. Heredity 40, 97–116 (1978).
Boomsma, D. I. Twin registers in Europe: An overview. Twin Res. 1, 34–51 (1998).
Busjahn, A. & Hur, Y. M. Twin registries: an ongoing success story. Twin Res. Hum. Genet. 9, 705 (2006).
Peltonen, L. GenomEUtwin: a strategy to identify genetic influences on health and disease. Twin Res. 6, 354–360 (2003).
Llewellyn, C. H., van Jaarsveld, C. H., Johnson, L., Carnell, S. & Wardle, J. Nature and nurture in infant appetite: analysis of the Gemini twin birth cohort. Am. J. Clin. Nutr. 91, 1172–1179 (2010).
Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer: analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000). In this study, twin data from Scandinavian twin registries were linked to national health records of cancer diagnosis to obtain heritability estimates for various types of cancer based on large twin samples.
Vink, J. M. et al. Cervix smear abnormalities: linking pathology data in female twins, their mothers and sisters. Eur. J. Hum. Genet. 19, 108–111 (2011).
De Geus, E. J. C. Introducing genetic psychophysiology. Biol. Psychol. 61, 1–10 (2002).
Mattay, V. S., Goldberg, T. E., Sambataro, F. & Weinberger, D. R. Neurobiology of cognitive aging: insights from imaging genetics. Biol. Psychol. 79, 9–22 (2008).
Peper, J. S., Brouwer, R. M., Boomsma, D. I., Kahn, R. S. & Hulshoff Pol, H. E. Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum. Brain Mapp. 28, 464–473 (2007).
Van Beijsterveldt, C. E. M. & Van Baal, G. C. M. Twin and family studies of the human electroencephalogram: a review and a meta-analysis. Biol. Psychol. 61, 111–138 (2002).
Koten, J. W. et al. Genetic contribution to variation in cognitive function: an fMRI study in twins. Science 323, 1737–1740 (2009).
van der Schot, A. C. et al. Influence of genes and environment on brain volumes in twin pairs concordant and discordant for bipolar disorder. Arch. Gen. Psychiatry 66, 142–151 (2009).
De Geus, E. J. C. et al. Intrapair differences in hippocampal volume in monozygotic twins discordant for the risk for anxiety and depression. Biol. Psychiatry 61, 1062–1071 (2007).
Falconer, D. S. Introduction to Quantitative Genetics (Ronald Press Co., 1960).
Tsang, T. M., Huang, J. T., Holmes, E. & Bahn, S. Metabolic profiling of plasma from discordant schizophrenia twins: correlation between lipid signals and global functioning in female schizophrenia patients. J. Proteome Res. 5, 756–760 (2006).
Harder, A. et al. Monozygotic twins with neurofibromatosis type 1 (NF1) display differences in methylation of NF1 gene promoter elements, 5′untranslated region, exon and intron 1. Twin Res. Hum. Genet. 13, 582–594 (2010).
Silventoinen, K. et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res. 6, 399–408 (2003).
Schousboe, K. et al. Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries. Twin Res. 6, 409–421 (2003).
Clausson, B., Lichtenstein, P. & Cnattingius, S. Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 107, 375–381 (2000).
Hyttinen, V., Kaprio, J., Kinnunen, L., Koskenvuo, M. & Tuomilehto, J. Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs. Diabetes 52, 1052–1055 (2003).
Kaprio, J. et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 35, 1060–1067 (1992).
Zdravkovic, S. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J. Intern. Med. 252, 247–254 (2002).
Zhang, S. et al. Genetic and environmental contributions to phenotypic components of metabolic syndrome: a population-based twin study. Obesity 17, 1581–1587 (2009).
Rahman, I. et al. Genetic dominance influences blood biomarker levels in a sample of 12,000 Swedish elderly twins. Twin Res. Hum. Genet. 12, 286–294 (2009).
Pedersen, N. L., Gatz, M., Berg, S. & Johansson, B. How heritable is Alzheimer's disease late in life? Findings from Swedish twins. Ann. Neurol. 55, 180–185 (2004).
Wirdefeldt, K., Gatz, M., Reynolds, C. A., Prescott, C. A. & Pedersen, N. L. Heritability of Parkinson disease in Swedish twins: a longitudinal study. Neurobiol. Aging 32, 1923–1928 (2011).
Mulder, E. J. et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res. 6, 422–431 (2003).
Hawkes, C. H. & MacGregor, A. J. Twin studies and the heritability of MS: a conclusion. Mult. Scler. 15, 661–667 (2009).
Faraone, S. V. et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol. Psychiatry 57, 1313–1323 (2005).
Lundstrom, S. et al. Autism spectrum disorders and autistic like traits: similar etiology in the extreme end and the normal variation. Arch. Gen. Psychiatry 69, 46–52 (2012).
Sullivan, P. F., Kendler, K. S. & Neale, M. C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003).
Sullivan, P. F., Neale, M. C. & Kendler, K. S. Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry 157, 1552–1562 (2000).
Peacock, M., Turner, C. H., Econs, M. J. & Foroud, T. Genetics of osteoporosis. Endocr. Rev. 23, 303–326 (2002).
Spector, T. D. & MacGregor, A. J. Risk factors for osteoarthritis: genetics. Osteoarthr. Cartil. 12 (Suppl. 1), 39–44 (2004).
MacGregor, A. J. et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 43, 30–37 (2000).
Thomsen, S. F., Van Der Sluis, S., Kyvik, K. O., Skytthe, A. & Backer, V. Estimates of asthma heritability in a large twin sample. Clin. Exp. Allergy 40, 1054–1061 (2010).
Ingebrigtsen, T. S. et al. Genetic influences on pulmonary function: a large sample twin study. Lung 189, 323–330 (2011).
Li, M. D., Cheng, R., Ma, J. Z. & Swan, G. E. A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98, 23–31 (2003).
Agrawal, A. & Lynskey, M. T. Are there genetic influences on addiction: evidence from family, adoption and twin studies. Addiction 103, 1069–1081 (2008).
Willer, C. J., Dyment, D. A., Risch, N. J., Sadovnick, A. D. & Ebers, G. C. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc. Natl Acad. Sci. USA 100, 12877–12882 (2003).
Halfvarson, J. Genetics in twins with Crohn's disease: less pronounced than previously believed? Inflamm. Bowel Dis. 17, 6–12 (2011).
Tanner, C. M. et al. Parkinson disease in twins. JAMA 281, 341–346 (1999).
Cardno, A. G. et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch. Gen. Psychiatry 56, 162–168 (1999).
Kendler, K. S. & Prescott, C. A. A population-based twin study of lifetime major depression in men and women. Arch. Gen. Psychiatry 56, 39–44 (1999).
Levy, F., Hay, D. A., McStephen, M., Wood, C. & Waldman, I. Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J. Am. Acad. Child Adolesc. Psychiatry 36, 737–744 (1997).
Rosenberg, R. E. et al. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch. Pediatr. Adolesc. Med. 163, 907–914 (2009).
This work was supported by the European Research Council (ERC 230374) and the Institute for Health and Care Research (EMGO+).
The authors declare no competing financial interests.
- 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).
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).
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.
The total set of RNA transcripts that are produced in a cell or tissue by transcription of DNA.
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.
The entire complement of proteins that are present in a cell, tissue or complete organism.
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.
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.
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.
(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.
The comprehensive study of the entire set of lipids in biological systems, such as cells, tissues and organs, using metabolomics techniques.
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).
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.
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.
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.
About this article
Cite this article
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
This article is cited by
Behavior Genetics (2022)
Nature Genetics (2021)
Nature Reviews Genetics (2021)