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DNA methylation as a potential novel target for the treatment of bipolar disorder

Non-genetic transgenerational transmission of bipolar disorder: targeting DNA methyltransferases

Molecular Psychiatry volume 21, pages 1653–1654 (2016)Cite this article

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Bipolar disorder (BD) has been shown to present a strong1 and complex2 genetic component, even though common variants found in genome-wide association studies still account for only a small fraction of BD heritability. In addition to the potential contribution of rare variants, the ‘heritability gap’ reported for BD3 suggests that non-genetic mechanisms have a role in its risk and onset. A plausible mechanism may include DNA methylation, which is an epigenetic modification catalyzed by DNA methyltransferases (DNMTs). Several studies have reported alterations in DNA methylation in patients with BD compared with controls,4, 5 and medications used in its treatment can impact methylation of specific genes and thereby modify gene expression as part of their mechanisms of action.6, 7 For instance, antidepressants have been shown to alter DNMT1 phosphorylation and thereby inhibit its activity. Particularly, this alteration is mediated by the effects of those medications on stress-related proteins and seems to be crucial for the resolution of symptoms in patients with depression.8

To pharmacologically modulate DNA methylation for the treatment of BD seems exciting and innovative for a series of reasons. As opposed to transiently altering the levels of specific neurotransmitters by means of modulating their receptors and/or transporters, altering DNA methylation can be permanent due to its relatively stable nature and the possibility of maintaining it with each cell division.9 In fact, recent studies on non-genetic transgenerational transmission of complex behavioral traits suggest DNA methylation as the key process in keeping certain phenotypes transmitted over several generations without further exposure to the initial environmental trigger.10 This has been suggested to partly account for the transmission of some trauma-induced effects from Holocaust survivors to their descendants,11 and animal studies have suggested that the effects of a prenatal exposure to immune activation, which increases the offspring’s risk to develop neuropsychiatric disorders, can be inherited through generations.12 Of note, even though this transgenerational mechanism has not been extensively reported in humans yet, some studies support the ‘intergenerational’ transmission of several traits.13, 14 Specifically, transgenerational effects have been consistently observed in humans,15, 16, 17 and transgenerational inheritance in human populations is increasingly becoming evident.18 In this sense, Tang et al.19 have recently suggested that DNA methylation patterns can be transmitted across generations during spermatogenesis in humans in a sequence-dependent manner. In other words, if applicable to BD, certain individuals might be at risk based on experiences that their ancestors lived, which could have changed methylation patterns in germ cells. Consequently, theoretically, altering DNA methylation could reverse the behavioral phenotype if it targets the genome of somatic cells, and it could also prevent the further transmission of the risk to the next generation if it targets germ cells. This is particularly relevant for the potential identification and/or treatment of high-risk subjects, such as first-degree relatives of BD patients, which would benefit from an opportunity for prevention and targeted early intervention based on their epigenetic profiling.

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Acknowledgements

The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from CNPq (JQ), FAPESC (JQ); Instituto Cérebro e Mente (JQ) and UNESC (JQ). JQ is a 1A CNPq Research Fellow. This study was also supported in part by grants from the Pat Rutherford, Jr Endowed Chair in Psychiatry (JCS), John S. Dunn Foundation from United States (JCS), and NIMH (R01MH085667).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Translational Psychiatry Program, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    G R Fries, C Walss-Bass & J Quevedo

  2. Department of Psychiatry and Behavioral Sciences, UT Center of Excellence on Mood Disorders, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    C Walss-Bass, J C Soares & J Quevedo

  3. Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    C Walss-Bass & J Quevedo

  4. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, Santa Catarina, Brazil

    J Quevedo

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Correspondence to J Quevedo.

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Fries, G., Walss-Bass, C., Soares, J. et al. Non-genetic transgenerational transmission of bipolar disorder: targeting DNA methyltransferases. Mol Psychiatry 21, 1653–1654 (2016). https://doi.org/10.1038/mp.2016.172

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