Aging, Environment, & DiseaseDNA Methylation and Hydroxymethylation

Implicating Methylation Variability in Depression

Implicating Methylation Variability in DepressionWhen Scott Kelly touched back down to Earth after nearly a year in space, scientists found that he was no longer strictly identical to his twin brother Mark [1]. While Scott’s DNA sequence was no different from his brother’s, he did have a number of epigenetic changes compared to Mark. Twin studies are a great way for scientists to understand the basis of many biological processes because monozygotic twins – twins coming from the same fertilized egg – have exactly the same DNA sequence. Therefore, any apparent differences between them, including susceptibility to disease, may be due to differences in their epigenome. A recent study by Córdova-Palomera et al took advantage of this feature of identical twins to identify regions of the human genome that have variable methylation in twins with depression compared to their unaffected siblings.

Epigenetic changes can result from the environment, in Scott’s case that environment was space, but they can also occur randomly over the lifetime of an individual [2]. These changes, called “stochastic changes,” are often seen as changes in DNA methylation [2]. Recently, scientists have found that in particular complex diseases like cancer, patients with the disease show variable levels of DNA methylation at certain sites compared to healthy people [3]. Meaning that, on a population level some patients with the disease will have extremely high levels of methylation at a particular site in the genome, but others will have very low levels of methylation at the same site [4]. This suggests that variation in DNA methylation can both be important for disease development and serve as a marker for the disease state.

Prior work [5] has suggested that twin patients with depression show an increase in DNA methylation variation at particular CpG sites, regions in the DNA sequence where a cytosine base is followed by a guanine base, compared to their healthy counterpart. Thus, in this study Córdova-Palomera et al aimed to validate that result by studying pairs of identical twins where one twin had depression and the other did not (discordant pairs) and to compare them to identical twins who both had depression (concordant pairs) and to identical twins who were both healthy.

The researchers analyzed the methylation level of over 450,000 CpG sites in the genome of 6 discordant pairs of twins, 4 concordant pairs, and 7 healthy pairs. They found that in the case of 1 set of discordant twins, the twin with depression had greater variability in DNA methylation at 13 different CpG sites across the entire genome compared to their healthy twin. They also saw that in a second set of discordant twins, the twin with depression also had greater variability in DNA methylation at 5 of these same CpG sites compared to their healthy sibling. Supporting these results, the researchers found that this difference in variability was not seen in concordant pairs of twins or in healthy pairs.

Additionally, the researchers found that many of these CpG sites were located in genes that have been shown to be involved in brain and nervous system functions in addition to neuropsychiatric disorders, indicating their possible relation to depression. In fact, one of the genes identified was GHSR, a ghrelin receptor. Ghrelin has been shown to be an important factor in anxiety, mood, and stress disorders [6]. The authors note that none of these genes have been implicated in depression before this study.

While this study is somewhat limited in that it only assessed 6 pairs of discordant twins, it does show that variability in DNA methylation can be found in patients with depression compared to their healthy counterparts. This technique of assessing variability in DNA methylation may lead to the identification of biomarkers for depression and greater insight into the biological pathways involved.

 

References:

Original article: Córdova-Palomera A, Palma-Gudiel H, Forés-Martos J, Tabarés-Seisdedos R, Fañanás L (2018). Epigenetic outlier profiles in depression: A genome-wide DNA methylation analysis of monozygotic twins. PLoS One, 13(11):e0207754. doi: 10.1371/journal.pone.0207754.

[1] Edwards M, Abadie L (2018, Jan 31). NASA Twins Study Investigators to Release Integrated Paper in 2018. NASA Human Research Strategic Communications, NASA. Updated 2018, Aug 16. https://www.nasa.gov/feature/nasa-twins-study-investigators-to-release-integrated-paper-in-2018

[2] Massicotte R, Whitelaw E, Angers B (2011). DNA methylation: A source of random variation in natural populations. Epigenetics, 6(4):421-7. DOI: 10.4161/epi.6.4.14532.

[3] Hansen KD, Timp W, Bravo HC, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E, Zhang K, Irizarry RA, Feinberg AP (2011). Increased methylation variation in epigenetic domains across cancer types. Nat Genet, 43(8):768-75. doi: 10.1038/ng.865.

[4] Teschendorff AE, Relton CL (2018). Statistical and integrative system-level analysis of DNA methylation data. Nat Rev Genet, 19(3):129-147. doi: 10.1038/nrg.2017.86.

[5] Córdova-Palomera A, Fatjó-Vilas M, Gastó C, Navarro V, Krebs MO, Fañanás L (2015). Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins. Transl Psychiatry, 5:e557. doi: 10.1038/tp.2015.49.

[6] Wittekind DA, Kluge M (2015). Ghrelin in psychiatric disorders – A review. Psychoneuroendocrinology, 52:176-94. doi: 10.1016/j.psyneuen.2014.11.013.

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Stephanie DeMarco

Stephanie DeMarco

Stephanie is a PhD candidate in Molecular Biology at the University of California, Los Angeles where she studies how the parasite Trypanosoma brucei regulates its social behavior. When she’s not wrangling her parasites in the lab, Stephanie likes to write about science, tap dance, and attempt to make the perfect plate of pasta carbonara.