Welcome to the epigenetic revolution

The first time the term epigenetics appeared in economics was in the year 2007, when Nobel laureate James Heckman wrote the article, "The economics, technology, and neuroscience of human capability formation (2007)." Heckman focuses on the influence that parental upbringing or early social environment have on the development of intellectual and emotional abilities. Heckman argues that one can think of childhood as the "critical period," the time when functioning brain connectivity is formed. Once formed, this connectivity can hardly change and affects behavior in general or in specific areas such as businesses.

But what is parenting anyway, and what does epigenetics have to do with it? But more importantly for the reader, what is epigenetics? I will answer these questions step by step.

What is genetics: Before I explain the concept of epigenetics, it is good to briefly tell what genetic research essentially means. I like to tell this using the work we have done ourselves in recent years, noting that colleagues in our faculty have also initiated their own genetic research projects (Beauchamp et al., 2011).

Our research focused, through hypothesis formation, on examining whether an association exists between a "candidate gene" and a phenotype. For example, neuroeconomists have found that developing expectations around rewarding versus non-rewarding events in the environment is associated with the functioning of the dopamine system (Schultz et al., 1997). We project this theory as a hypothesis onto genetics. For example, we have examined that a variant of a gene that partly influences the production of dopamine receptors (the well-known DRD4 ^7R+) may affect how people value their environment. The latter is then the phenotype that, for example, is more or less attentive to reward opportunities. Another hypothesis is: because the oxytocin system influences how people form relationships with each other, one variant of an oxytocin receptor gene (the OXTR AA versus AG/GG variant) may have an association with how people form relationships. The latter, in turn, is the phenotype and may mean that a person is more or less social (Donaldson and Young, 2008). We have indeed found these associations in several studies, but that does not mean we could always replicate them. These are also called "false positives.

Low replicability of genetic studies: Low replicability is a very well-known phenomenon within genetics: for example, meta-studies have shown that neither the DRD4 gene just mentioned nor the OXTR gene have a significant association with appreciation of the environment or with social behavior, respectively (Pappa et al., 2014; Bakermans-Kranenburg and Van IJzendoorn, 2014). Incidentally, the researchers doing the meta-studies respond quite harshly to people who loudly proclaim their findings surrounding the association between a "candidate gene" and a phenotype from small test studies. For example, we read the following statement from the research group of Professor Tiemeier of Erasmus MC: "In summary, this systematic review indicates that it is not yet possible to draw definitive conclusions about the functionality of DRD4 VNTRs polymorphisms. Despite the wealth of studies, we appear to remain in the discovery phase of behavioral research employing DRD4 VNTRs. A moratorium should be declared on the singling out of the 7-repeat - the 'Magnificent Seven' - at least until the application of multidisciplinary principles shed light on the functionality of the different variants." (Pappa et al., 2015, p. 184). These scientists do not mince words, but they do adhere to the latest guidelines of the KNAW, which now holds that sound science should not always be discoverable but should also and above all be based on replicability (see NOS article in the bibliography).

There are many reasons why replicating genetic studies are difficult. For starters, geneticists do not study a single gene, but a base pair of a gene, also called a SNP, and in humans, the length of a gene can range from a few hundred base pairs to a few million. Furthermore, it is estimated that humans possess around 20,500 genes. Taking into account the fact that genes make proteins that have enormous influence on intracellular dynamics in neurons/cells, a finding of an association between a SNP and a phenotype is a long shot. Thereby, different genes play a role for the same phenotype, which is also called polygeny.

The social environment also plays an important role in the association of a gene with a phenotype: if one nasally administers the hormone oxytocin, it has a binding but also a hating effect, depending on whether a person is in the in-group or out-group (De Dreu, et al., 2010). Furthermore, there are also interaction effects between genes based on the dopamine peptide hypothesis (Shamay-Tsoory and Abu-Akel, 2016). For example, we showed that in carriers of a DRD4 variant(the variant associated with little attention to rewards in the environment) and an OXTR variant(in this case, the AA variant that represents aloofness toward others), this was actually associated with a greater predisposition to empathize with how other people think. In addition, Belsky and Pluess (2009), among others, have developed the "differential susceptibility hypothesis," showing that, depending on parental upbringing, carriers of a variant of a gene may experience both long-term benefits and disadvantages. Briefly, it appears that because carriers of the DRD4 ^7R+ variant are sensitive to rewards, they will be happier later with a supportive environment during childhood, but will be less happy later with a harsher and less supportive social environment.

What is epigenetics: This brings us to the role of epigenetics. The genetic thinking we have just outlined always assumes the genetics dogma: the idea is that there is a genetic code, i.e., the DNA (which consists of base-pairs linked to a phosphate-deoxyribose backbone), which is turned on by activation via transcription factors of that gene's promoter, after which the gene can be read (RNA) so that it can be translated and converted into amino acids. From these, proteins are made that then affect how cells/neurons function within organs such as the liver or brain. The well-known DNA chain is shown below.

Now it turns out that this is only half the truth: DNA is a very long chain of base-pairs in the nucleus of each cell, but it is wrapped on chromosomes. Those chromosomes also contain histones around which the DNA is wrapped, forming a nucleosome. This ensures that the DNA, which we just mentioned is very long and rolled up in the nucleosome, thus takes up very little space. Now the problem is that if it is very tightly coiled, it is difficult for transcription factors to turn on the gene transcription just mentioned. So enzymatic work is needed to loosen the winding of DNA around the histones a bit so that transcription factors can get to the DNA (see figure below).

On top of that, promoters of a gene also have methylation, which makes it difficult for transcription factors to reach the promoter (this turning on of the promoter is necessary for turning on the gene transcription turn on so that proteins are produced for cell functioning). Especially sociologists are very interested in methylation (Landecker and Panofsky, 2013), but also biologists, especially those who work about social behavior (Meaney, 2001). It is mainly on the basis of the latter work that the economist Heckman (2007) based his ideas.

Epigenetics and parenting: Some years ago, people from Meaney's group (Meaney, 2001) researched the influence of maternal mice care on their just-born baby mice. Experimentally investigating the influence of parenting in humans is unethical, hence the use of mice, or animal experiments. In these, the mice were raised by a stable mother or a neurotic mother. When mammals, including mice, experience stress, they make cortisol through the activation of the stress system, or hypothalamic-pituitary-adrenal (HPA) axis. Hence, the baby mice seek warmth from the mother mouse. This gives them rest and stops the stress system. Stopping the stress system can only occur if the mouse has functioning receptors in the hippocampus for cortisol (see figure below).

Of interest, it was found that in mice that were well raised by a ´good mouse mother´ the glucocorticoid receptor (the Nr3C1) functioned properly because the methylation on the promoter had been removed. In mice that had been poorly raised, however, the methylation was found to remain in place, preventing the gene from being read and translated to create receptors. This discovery has led to new research on how parenting affects epigenetic mechanisms, in both animals and humans.

Epigenetic discovery in humans: Based on this study in mice, we looked at attachment styles and in particular whether attachment styles are related to the methylation of the glucocorticoid receptor needed to block in the hippocampus the activation of the HPA axis - or in other words, to stop the stress response.

Attachment styles arise from parental upbringing during childhood. One mainly distinguishes between three styles: secure, avoidant and fearful attachment. Secure attachment means that people were raised in a warm nest, where they found protection from parents when they experienced stress. Avoidant attachment occurs when parents provided little support and literally reacted coldly to their children's stress. As a result, they did not learn to seek support in times of distress. Anxious attachment occurs when parents are inconsistent, meaning they are sometimes warm but then cold and this causes anxious uncertainty in people whether others can give them security. Needless to say, this greatly affects how people interact with others later in life, which is why Heckman talks about critical periods.

We examined whether in anxious or avoidant attached people, methyl rings would hang from the promoter of glucocorticoid receptors (Ein-Dor et al., 2018). To our surprise, this was true, but only in the avoidantly attached people. These attachment styles are considered not readily changeable, as they arise during critical moments. And so we have taken a first step toward what Heckman calls "the role of parenting and the role epigenetics plays in it. We also now understand that if genes have epigenetic markers it is understandable why genetics can be so little predictive and why so many genetics studies are not replicable. If gene transcription is not functioning due to epigenetic markings, one also cannot produce the necessary proteins for cells to function properly and that in turn affects phenotypes or behavior.Economically, this is important and I am just giving an example here: Avoidantly attached people often suffer from stress and they are also not attached to people and perhaps not to ideas. So they are open to change because they have no attachment to groups that carry or defend the ideas. Now if we know that there are epigenetic mechanisms for that, we can molecularly reason why avoidant attached people behave systematically.

We are currently applying for a grant to further analyze these initial findings. Because if we understand the epigenetic mechanisms of attachment styles, we may be able to change people's attachment styles as well, should that be desirable.

Bibliography
Bakermans-Kranenburg, M. J., & Van IJzendoorn, M. H. (2014). A sociability gene? Meta-analysis of oxytocin receptor genotype effects in humans. Psychiatric genetics, 24(2), 45-51.

Beauchamp, Jonathan P., David Cesarini, Magnus Johannesson, Matthijs JHM van der Loos, Philipp D. Koellinger, Patrick JF Groenen, James H. Fowler, Niels J. Rosenquist, Roy A. Thurik, and Nicholas A. Christakis. "Molecular genetics and economics." The Journal of Economic Perspectives 25, no. 4 (2011): 57-82.

Belsky, J., & Pluess, M. (2009). Beyond Diathesis-Stress: Differential Susceptibility to Environmental Influences. Psychological Bulletin, 135(6), 885-908.

De Dreu, C. K., Greer, L. L., Handgraaf, M. J., Shalvi, S., Van Kleef, G. A., Baas, M., ... & Feith, S. W. (2010). The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science, 328(5984), 1408-1411.

Donaldson, Z. R., & Young, L. J. (2008). Oxytocin, vasopressin, and the neurogenetics of sociality. Science, 322(5903), 900-904.
Ein-Dor, T., W. JMI Verbeke, M. Mokry, & P. Vrticka (2018). "Epigenetic Modification of the Oxytocin and Glucocorticoid Receptor Genes is Linked to Attachment Avoidance in Young Adults." (2018).

Heckman, J. J. (2007). The economics, technology, and neuroscience of human capability formation. Proceedings of the national Academy of Sciences, 104(33), 13250-13255.

Landecker, H., & Panofsky, A. (2013). From social structure to gene regulation, and back: A critical introduction to environmental epigenetics for sociology. Annual Review of Sociology, 39, 333-357.

Meaney, M. J. (2001). Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annual review of neuroscience, 24(1), 1161-1192.

Pappa, I., Mileva-Seitz, V. R., Bakermans-Kranenburg, M. J., Tiemeier, H., & van Ijzendoorn, M. H. (2015). The magnificent seven: A quantitative review of dopamine receptor d4 and its association with child behavior. Neuroscience & Biobehavioral Reviews, 57, 175-186.

Schultz, W., Dayan, P., & Montague, P. R. (1997). A neural substrate of prediction and reward. Science, 275(5306), 1593-1599.

Shamay-Tsoory, S. G., & Abu-Akel, A. (2016). The social salience hypothesis of oxytocin. Biological psychiatry, 79(3), 194-202.

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