The importance of twin studies in understanding the early life origins of chronic disease

ISNN: 2652-5518
By Jeffery M. Craig

Main points 

  • Many risks for chronic disease derive from genes or from the environment encountered in early life – including in the womb.
  • Twin studies show that the supply of blood from the mother, through the placenta and cords to the fetuses, can differ, and that this nonshared risk is more important than the shared risks.
  • Twins must be included in studies of early life origins of chronic disease.

 

Summary

We now know that many risks for chronic disease originate in early life. All of us are born with a genetic risk inherited from our parents and an environmental risk from our time spent in the womb. Twin studies show that this environmental risk is split unevenly, with the lion’s share being from the environment that twins don’t share – the supply of blood from the mother, through the placenta and cords to the individual, the so-called “nonshared environment”. Many studies focus on the link between within-pair discordance for chronic disease in adulthood and within-pair discordance in birthweight, as this acts as a proxy for differential supply of nutrients, oxygen and other factors influencing growth in utero. Here I review studies of these relationships and shed light on some of the mechanisms behind them.

Suggested citation: Craig, J.M. The importance of twin studies in understanding the early life origins of chronic disease. Conversations in Twins Research, Twins Research Australia, Melbourne, 2018.https://www.twins.org.au/research/tools-and-resources/125-conversation-in-twin-research/373-the-importance-of-twin-studies-in-understanding-the-early-life-origins-of-chronic-disease

Background

The findings of David Barker that low birth weight, a proxy for compromised growth rate in utero, is linked to a later risk of heart disease [1], sparked a new field of research that is flourishing today. The field is known as the Developmental Origins of Health and Disease [2], and by a more user-friendly name: “The First Thousands Days” [3]. In a nutshell, evidence has accumulated that the environment encountered in early life contributes significantly to risk for chronic diseases, including heart disease, type 2 diabetes, allergies, psychiatric disorders and some cancers. The rationale behind such research is that if modifiable risk factors are discovered, interventions that avoid, counteract or enhance such factors could be designed and implemented.

What the research tells us

Twin studies have contributed much to our understanding of the early life origins of disease [4]. First and foremost, we know that identical twins can have significantly different birthweights and can even be born discordant for infection [5]. This tells us that twins can encounter different environments in the womb. In longitudinal twin studies, within-pair differences in birth weight have predicted within-pair differences in disorders as diverse as schizophrenia [6], attention problems [7], blood pressure [8] and type 2 diabetes [9]. It is unlikely that birth weight per se is causing these disorders, so what could? The answer lies in the route taken by beneficial factors such as nutrients and oxygen, and harmful factors such as toxins, from the mother to the fetus.

All fraternal twins and a third of identical twins have their own placenta, and these can come in many shapes and sizes. Placental dimensions have previously been linked with risk for chronic disease in singletons [10]. Two-thirds of identical twins share a single placenta; in these cases, twins have their own blood supply but each twin’s share of the placenta can be quite different. Every twin also has its own umbilical cord and these can come in different widths and lengths; the shorter and fatter the cord, the faster the blood flows to the twin. Moreover, placenta structure can differ within twin pairs. There are no reasons to believe that such relationships won’t hold for singletons.

There is still a lot to be learned about how the environment that each fetus encounters in the womb can affect its growth and risk for chronic disease. However, we know that identical twins are born with differences in their epigenetics (literally “above genetics” [11]), which involve small molecules that bind to genes and influence their activity. Such molecules are “remembered” when cells divide, are important for guiding our development in the womb, and can be influenced by environmental factors such as stress, nutrition and smoking, which suggests that they could mediate the long-term effects of the environments encountered in the womb.

For some chronic conditions, such as adult bone mineral density, there is no evidence at all for a correlation between within-pair birth weight discordance and disease discordance in adulthood [12]. Twins often catch up with each other with respect to weight, and it is unknown whether this reduces or enhances discordance for future disease risk. Twin pairs can also be influenced strongly and similarly by postnatal factors such as maternal care and breastfeeding, which in some situations could dwarf the effects of a different birth weight. Nevertheless, a recent analysis of data about 28 chronic diseases from more than 150,000 European twins found that the sum of shared genetics and shared environment accounted on average for only 18.5% of phenotypic variation in these diseases, leaving nonshared, twin-specific environments with the lion’s share of the cause [13]. Clearly, twin-specific factors are worth research investment.

Current and future implications of research into the early life origins of chronic disease

The findings reviewed here have major implications for human health and will be of interest to all who come into contact with twins, from midwives to general practitioners, paediatricians and teachers. As all twins share some genetic sequence and some shared environments, in pairs in which one twin presents with a health condition, the co-twin should be closely monitored for signs and symptoms. However, it should be realised that some of these pairs will remain forever discordant, due to the environments that they alone have encountered.

Data from associations of birth weight with risk for chronic disease tell us that we already have some idea at birth of an individual’s risk for disease. Combined with genetic and epigenetic data, this could mean that we could one day be able to predict each person’s risk for chronic disease and in doing so, implement preventive strategies early in life when they might be more effective.

Conclusion

Research has begun to show that despite earlier assumptions to the contrary, twins do not always share the same environment in the womb, and that in cases where they don’t, we can learn a lot about the origins of chronic diseases. This means that wherever possible, researchers need to include twins in studies of early life origins of chronic disease.

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About the author

Associate Professor Jeffrey Craig works in the Centre for Molecular and Medical Research at the Deakin University School of Medicine in Geelong, Victoria.

References

  1. Barker, D.J., and Osmond C. Low birth weight and hypertension. British Medical Journal, 1988. 297(6641):134-5.
  2. Gluckman, P.D., M.A. Hanson, and T. Buklijas. A conceptual framework for the developmental origins of health and disease. Journal of Developmental Origins of Health and Disease, 2010. 1(1):6-18.
  3. 1,000 Days. Why 1,000 Days. https://thousanddays.org/the-issue/why-1000-days/
  4. Morley, R. and T. Dwyer. Studies of twins: what can they tell us about the fetal origins of adult disease? Paediatric and Perinatal Epidemiology, 2005. 19 Suppl 1:2-7.
  5. Jamieson, D.J., J.S. Read, A.P. Kourtis, T.M. Durant, M.A. Lampe, and K.L. Dominguez. Cesarean delivery for HIV-infected women: recommendations and controversies. American Journal of Obstetrics and Gynecology, 2007. 197(3 Suppl):S96-100.
  6. Nilsson, E, G. Stalberg, P. Lichtenstein, S. Cnattingius, P.O. Olausson, and C.M. Hultman. Fetal growth restriction and schizophrenia: a Swedish twin study. Twin Research and Human Genetics. 2005. 8(4):402-8.
  7. Groen-Blokhuis, MM, C.M. Middeldorp, C.E. van Beijsterveldt, and D.I. Boomsma. Evidence for a causal association of low birth weight and attention problems. Journal of the American Academy of Child and Adolescent Psychiatry, 2011. 50(12):1247-54 e2.
  8. Dwyer, T., L. Blizzard, R. Morley, and A.L. Ponsonby. Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study. British Medical Journal, 1999. 319(7221):1325-9.
  9. Iliadou, A., S. Cnattingius, and P. Lichtenstein. Low birthweight and Type 2 diabetes: a study on 11 162 Swedish twins. International Journal of Epidemiology, 2004. 33(5):948-53; discussion 53-4.
  10. Thornburg K.L., and N. Marshall. The placenta is the center of the chronic disease universe. American Journal of Obstetrics and Gynecology, 2015. 213(4 Suppl):S14-20.
  11. Ollikainen, M., K.R. Smith, E.J. Joo, H.K. Ng, R. Andronikos, B. Novakovic, et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Human Molecular Genetics, 2010. 19(21):4176-88.
  12. Frost, M., I. Petersen, T.L. Andersen, B.L. Langdahl, T. Buhl, L. Christiansen, et al. Birth weight and adult bone metabolism are unrelated: results from birth weight-discordant monozygotic twins. Journal of Bone and Mineral Research, 2013. 28(12):2561-9.
  13. Rappaport, S.M. Genetic factors are not the major causes of chronic diseases. PLoS One, 2016. 11(4): e0154387.

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