Hostname: page-component-78c5997874-g7gxr Total loading time: 0 Render date: 2024-11-10T05:23:09.019Z Has data issue: false hasContentIssue false
  • English
  • Français

An epigenetic pathway approach to investigating associations between prenatal exposure to maternal mood disorder and newborn neurobehavior

Published online by Cambridge University Press:  02 August 2018

Elisabeth Conradt ,
Daniel E. Adkins ,
Sheila E. Crowell ,
Catherine Monk  and
Michael S. Kobor
Elisabeth Conradt*
Affiliation:
University of Utah
Daniel E. Adkins
Affiliation:
University of Utah
Sheila E. Crowell
Affiliation:
University of Utah
Catherine Monk
Affiliation:
Columbia University Medical Center New York State Psychiatric Institute
Michael S. Kobor
Affiliation:
University of British Columbia
*
Address correspondence and reprint requests to: Elisabeth Conradt, University of Utah, Department of Psychology, 380 South 1530 East BEHS 602, Salt Lake City, UT 84112; E-mail: elisabeth.conradt@psych.utah.edu.
Get access Rights & Permissions [Opens in a new window]

Abstract

Following recent advances in behavioral and psychiatric epigenetics, researchers are increasingly using epigenetic methods to study prenatal exposure to maternal mood disorder and its effects on fetal and newborn neurobehavior. Despite notable progress, various methodological limitations continue to obscure our understanding of the epigenetic mechanisms underpinning prenatal exposure to maternal mood disorder on newborn neurobehavioral development. Here we detail this problem, discussing limitations of the currently dominant analytical approaches (i.e., candidate epigenetic and epigenome-wide association studies), then present a solution that retains many benefits of existing methods while minimizing their shortcomings: epigenetic pathway analysis. We argue that the application of pathway-based epigenetic approaches that target DNA methylation at transcription factor binding sites could substantially deepen our mechanistic understanding of how prenatal exposures influence newborn neurobehavior.

Type
Special Issue Articles
Information
Development and Psychopathology , Volume 30 , Special Issue 3: Developmental Origins of Psychopathology: Mechanisms, Processes, and Pathways Linking the Prenatal Environment to Postnatal Outcomes , August 2018 , pp. 881 - 890
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

This manuscript was supported by the National Institute of Mental Health under Award Number R21MH109777 (to S.C. and E.C.), a Career Development Award from the National Institute on Drug Abuse 7K08DA038959-02 (to E.C.), and a grant from the University of Utah Consortium for Families and Health Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institute on Drug Abuse, or the National Institutes of Health.

References

Adkins, D. E., Rasmussen, K. M., & Docherty, A. R. (2017). Social epigenetics and human behavior. In Hopcroft, R. (Ed.), Oxford handbook of evolution, biology, and society. Oxford: Oxford University Press.Google Scholar
Appleton, A. A., Lester, B. M., Armstrong, D. A., Lesseur, C., & Marsit, C. J. (2015). Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior. Psychoneuroendocrinology, 52, 32–42. doi:10.1016/j.psyneuen.2014.11.004Google Scholar
Beijers, R., Buitelaar, J. K., & de Weerth, C. (2014). Mechanisms underlying the effects of prenatal psychosocial stress on child outcomes: Beyond the HPA axis. European Child and Adolescent Psychiatry, 23, 943–956. doi:10.1007/s00787-014-0566-3Google Scholar
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate—A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B Methodological, 57, 289–300.Google Scholar
Bird, A. (2007). Perceptions of epigenetics. Nature, 447, 396–398. doi:10.1038/nature05913Google Scholar
Bock, C. (2012). Analysing and interpreting DNA methylation data. Nature Reviews Genetics, 13, 705–719. doi:10.1038/nrg3273Google Scholar
Boyce, W. T., & Kobor, M. S. (2015). Development and the epigenome: The “synapse” of gene-environment interplay. Developmental Science, 18, 1–23. doi:10.1111/desc.12282Google Scholar
Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., … Murphy, S. K. (2017). Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives, 125. doi:10.1289/EHP595Google Scholar
Bromer, C., Marsit, C. J., Armstrong, D. A., Padbury, J. F., & Lester, B. (2013). Genetic and epigenetic variation of the glucocorticoid receptor (NR3c1) in placenta and newborn neurobehavior. Developmental Psychobiology, 55, 673–683. doi:10.1002/dev.21061Google Scholar
Buss, C., Davis, E. P., Shahbaba, B., Pruessner, J. C., Head, K., & Sandman, C. A. (2012). Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proceedings of the National Academy of Sciences, 109, E1312–E1319. doi:10.1073/pnas.1201295109Google Scholar
Conradt, E. (2017). Using principles of behavioral epigenetics to advance research on early-life stress. Child Development Perspectives, 11, 107–112. doi:10.1111/cdep.12219Google Scholar
Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A., & Marsit, C. J. (2013). The roles of DNA methylation of NR3c1 and 11β–HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigentics, 8, 1321–1329. doi:10.4161/epi.26634Google Scholar
Davies, M. N., Krause, L., Bell, J. T., Gao, F., Ward, K. J., Wu, H., … Wang, J. (2014). Hypermethylation in the ZBTB20 gene is associated with major depressive disorder. Genome Biology, 15, R56. doi:10.1186/gb-2014-15-4-r56Google Scholar
Davis, E. P., Glynn, L. M., Schetter, C. D., Hobel, C., Chicz-Demet, A., & Sandman, C. A. (2007). Prenatal exposure to maternal depression and cortisol influences infant temperament. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 737–746. doi:10.1097/chi.0b013e318047b775Google Scholar
De Bellis, M. D., Chrousos, G. P., Dorn, L. D., Burke, L., Helmers, K., Kling, M. A., … Putnam, F. W. (1994). Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls. Journal of Clinical Endocrinology & Metabolism, 78, 249–255. doi:10.1210/jcem.78.2.8106608Google Scholar
de Goede, O. M., Razzaghian, H. R., Price, E. M., Jones, M. J., Kobor, M. S., Robinson, W. P., & Lavoie, P. M. (2015). Nucleated red blood cells impact DNA methylation and expression analyses of cord blood hematopoietic cells. Clinical Epigenetics, 7. doi:10.1186/s13148-015-0129-6Google Scholar
de Moor, M. H. M., van den Berg, S. M., Verweij, K. J. H., Krueger, R. F., Luciano, M., Arias Vasquez, A., … Boomsma, D. I. (2015). Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder. JAMA Psychiatry, 72, 642. doi:10.1001/jamapsychiatry.2015.0554Google Scholar
Dempster, E. L., Wong, C. C. Y., Lester, K. J., Burrage, J., Gregory, A. M., Mill, J., & Eley, T. C. (2014). Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biological Psychiatry, 76, 977–983. doi:10.1016/j.biopsych.2014.04.013Google Scholar
Docherty, A. R., Moscati, A., Adkins, D. E., Wallace, G. T., Kumar, G., Riley, B. P., … Bacanu, S.-A. (2017). Proof of concept: Molecular prediction of schizophrenia risk. Unpublished manuscript.Google Scholar
Docherty, A. R., Moscati, A., Dick, D., Savage, J. E., Salvatore, J. E., Cooke, M., … Kendler, K. S. (2017). Polygenic prediction of the phenome, across ancestry, in emerging adulthood. Psychological Medicine, 27, 1–10. doi:10.1101/124651Google Scholar
Essex, M. J., Klein, M. H., Cho, E., & Kalin, N. H. (2002). Maternal stress beginning in infancy may sensitize children to later stress exposure: Effects on cortisol and behavior. Biological Psychiatry, 52, 776–784.Google Scholar
Essex, M. J., Thomas Boyce, W., Hertzman, C., Lam, L. L., Armstrong, J. M., Neumann, S. M. A., & Kobor, M. S. (2013). Epigenetic vestiges of early developmental adversity: Childhood stress exposure and DNA methylation in adolescence: Epigenetic vestiges of early adversity. Child Development, 84, 58–75. doi:10.1111/j.1467-8624.2011.01641.xGoogle Scholar
Gandal, M. J., Leppa, V., Won, H., Parikshak, N. N., & Geschwind, D. H. (2016). The road to precision psychiatry: Translating genetics into disease mechanisms. Nature Neuroscience, 19, 1397–1407. doi:10.1038/nn.4409Google Scholar
Glynn, L. M., Davis, E. P., & Sandman, C. A. (2013). New insights into the role of perinatal HPA-axis dysregulation in postpartum depression. Neuropeptides, 47, 363–370. doi:10.1016/j.npep.2013.10.007Google Scholar
Goodman, S. H., Rouse, M. H., Connell, A. M., Broth, M. R., Hall, C. M., & Heyward, D. (2011). Maternal depression and child psychopathology: A meta-analytic review. Clinical Child and Family Psychology Review, 14, 1–27. doi:10.1007/s10567-010-0080-1Google Scholar
Greally, J. M. (2018). A user's guide to the ambiguous word “epigenetics.” Nature Reviews Molecular Cell Biology, 19, 207–208. doi:10.1038/nrm.2017.135Google Scholar
Heijmans, B. T., Tobi, E. W., Stein, A. D., Putter, H., Blauw, G. J., Susser, E. S., … Lumey, L. H. (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences, 105, 17046–17049. doi:10.1073/pnas.0806560105Google Scholar
Heim, C., & Nemeroff, C. B. (2001). The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies. Biological Psychiatry, 49, 1023–1039. doi:10.1016/S0006-3223(01)01157-XGoogle Scholar
Herman, J. P., & Spencer, R. (1998). Regulation of hippocampal glucocorticoid receptor gene transcription and protein expression in vivo. Journal of Neuroscience, 18, 7462–7473.Google Scholar
Houseman, E., Accomando, W. P., Koestler, D. C., Christensen, B. C., Marsit, C. J., Nelson, H. H., … Kelsey, K. T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics, 13, 86. doi:10.1186/1471-2105-13-86Google Scholar
Huber, W., Carey, V. J., Gentleman, R., Anders, S., Carlson, M., Carvalho, B. S., … Morgan, M. (2015). Orchestrating high-throughput genomic analysis with Bioconductor. Nature Methods, 12, 115–121. doi:10.1038/nmeth.3252Google Scholar
Ishimoto, H., & Jaffe, R. B. (2011). Development and function of the human fetal adrenal cortex: A key component in the feto-placental unit. Endocrine Reviews, 32, 317–355. doi:10.1210/er.2010-0001Google Scholar
Jones, P. A. (2012). Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nature Reviews Genetics, 13, 484–492. doi:10.1038/nrg3230Google Scholar
Kasckow, J. W., Baker, D., & Geracioti, T. D. (2001). Corticotropin-releasing hormone in depression and post-traumatic stress disorder. Peptides, 22, 845–851. doi:10.1016/S0196-9781(01)00399-0Google Scholar
Keating, D. P. (2016). Transformative role of epigenetics in child development research: Commentary on the Special Section. Child Development, 87, 135–142. doi:10.1111/cdev.12488Google Scholar
Kinsella, M. T., & Monk, C. (2009). Impact of maternal stress, depression and anxiety on fetal neurobehavioral development. Clinical Obstetrics and Gynecology, 52, 425–440. doi:10.1097/GRF.0b013e3181b52df1Google Scholar
Labonté, B., Suderman, M., Maussion, G., Lopez, J. P., Navarro-Sánchez, L., Yerko, V., … Turecki, G. (2013). Genome-wide methylation changes in the brains of suicide completers. American Journal of Psychiatry, 170, 511–520. doi:10.1176/appi.ajp.2012.12050627Google Scholar
Labonté, B., Suderman, M., Maussion, G., Navaro, L., Yerko, V., Mahar, I., … Turecki, G. (2012). Genome-wide epigenetic regulation by early-life trauma. Archives of General Psychiatry, 69. doi:10.1001/archgenpsychiatry.2011.2287Google Scholar
Lappalainen, T., & Greally, J. M. (2017). Associating cellular epigenetic models with human phenotypes. Nature Reviews Genetics, 18, 441–451. doi:10.1038/nrg.2017.32Google Scholar
Lester, B. M., Conradt, E., & Marsit, C. (2016). Introduction to the Special Section on epigenetics. Child Development, 87, 29–37. doi:10.1111/cdev.12489Google Scholar
Maccani, J. Z. J., Koestler, D. C., Lester, B., Houseman, E. A., Armstrong, D. A., Kelsey, K. T., & Marsit, C. J. (2015). Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environmental Health Perspectives, 123, 723–729. doi:10.1289/ehp.1408561Google Scholar
Maccari, S., Krugers, H. J., Morley-Fletcher, S., Szyf, M., & Brunton, P. J. (2014). The consequences of early-life adversity: Neurobiological, behavioural and epigenetic adaptations. Journal of Neuroendocrinology, 26, 707–723. doi:10.1111/jne.12175Google Scholar
Mansell, T., Vuillermin, P., Ponsonby, A.-L., Collier, F., Saffery, R., Barwon Infant Study Investigator Team, & Ryan, J. (2016). Maternal mental well-being during pregnancy and glucocorticoid receptor gene promoter methylation in the neonate. Development and Psychopathology, 28(4, pt. 2), 1421–1430. doi:10.1017/S0954579416000183Google Scholar
Marsit, C. J., Maccani, M. A., Padbury, J. F., & Lester, B. M. (2012). Placental 11-beta hydroxysteroid dehydrogenase methylation is associated with newborn growth and a measure of neurobehavioral outcome. PLOS, 1, e33794. doi:10.1371/journal.pone.0033794Google Scholar
McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P. A., & Hirschhorn, J. N. (2008). Genome-wide association studies for complex traits: Consensus, uncertainty and challenges. Nature Reviews Genetics, 9, 356–369. doi:10.1038/nrg2344Google Scholar
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., … Meaney, M. J. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342–348. doi:10.1038/nn.2270Google Scholar
Meaney, M. J. (2010). Epigenetics and the biological definition of gene × environment interactions. Child Development, 81, 41–79.Google Scholar
Monk, C., Feng, T., Lee, S., Krupska, I., Champagne, F. A., & Tycko, B. (2016). Distress during pregnancy: Epigenetic regulation of placenta glucocorticoid-related genes and fetal neurobehavior. American Journal of Psychiatry, 173, 705–713. doi:10.1176/appi.ajp.2015.15091171Google Scholar
Monk, C., Spicer, J., & Champagne, F. A. (2012). Linking prenatal maternal adversity to developmental outcomes in infants: The role of epigenetic pathways. Development and Psychopathology, 24, 1361–1376. doi:10.1017/S0954579412000764Google Scholar
Murphy, S. E., Braithwaite, E. C., Hubbard, I., Williams, K. V., Tindall, E., Holmes, E. A., & Ramchandani, P. G. (2015). Salivary cortisol response to infant distress in pregnant women with depressive symptoms. Archives of Women's Mental Health, 18, 247–253. doi:10.1007/s00737-014-0473-0Google Scholar
Nagy, C., Suderman, M., Yang, J., Szyf, M., Mechawar, N., Ernst, C., & Turecki, G. (2015). Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Molecular Psychiatry, 20, 320–328. doi:10.1038/mp.2014.21Google Scholar
Nigg, J. T. (2016). Where do epigenetics and developmental origins take the field of developmental psychopathology? Journal of Abnormal Child Psychology, 44, 405–419. doi:10.1007/s10802-015-0121-9Google Scholar
Painter, R. C., Westendorp, R. G. J., de Rooij, S. R., Osmond, C., Barker, D. J. P., & Roseboom, T. J. (2008). Increased reproductive success of women after prenatal undernutrition. Human Reproduction, 23, 2591–2595. doi:10.1093/humrep/den274Google Scholar
Paquette, A. G., Houseman, E. A., Green, B. B., Lesseur, C., Armstrong, D. A., Lester, B., & Marsit, C. J. (2016). Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics, 11, 603–613. doi:10.1080/15592294.2016.1195534Google Scholar
Paquette, A. G., Lester, B. M., Lesseur, C., Armstrong, D. A., Guerin, D. J., Appleton, A. A., & Marsit, C. J. (2015). Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics, 7, 767–779. doi:10.2217/epi.15.28Google Scholar
Salm, A. K., Pavelko, M., Krouse, E. M., Webster, W., Kraszpulski, M., & Birkle, D. L. (2004). Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress. Developmental Brain Research, 148, 159–167. doi:10.1016/j.devbrainres.2003.11.005Google Scholar
Sandman, C. A., & Davis, E. P. (2012). Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Review of Endocrinology and Metabolism, 7, 445–459. doi:10.1586/eem.12.33Google Scholar
Sandman, C. A., Glynn, L. M., & Davis, E. P. (2016). Neurobehavioral consequences of fetal exposure to gestational stress. In Reissland, N. & Kisilevsky, B. S. (Eds.), Fetal development (pp. 229–265). London: Springer.Google Scholar
Sirianni, R., Rehman, K. S., Carr, B. R., Parker, C. R., & Rainey, W. E. (2005). Corticotropin-releasing hormone directly stimulates cortisol and the cortisol biosynthetic pathway in human fetal adrenal cells. Journal of Clinical Endocrinology and Metabolism, 90, 279–285. doi:10.1210/jc.2004-0865Google Scholar
Stroud, L. R., Papandonatos, G. D., Salisbury, A. L., Phipps, M. G., Huestis, M. A., Niaura, R., … Lester, B.M. (2016). Epigenetic regulation of placental NR3c1: Mechanism underlying prenatal programming of infant neurobehavior by maternal smoking? Child Development, 87, 49–60. doi:10.1111/cdev.12482Google Scholar
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., … Mesirov, J. P. (2005). Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences, 102, 15545–15550. doi:10.1073/pnas.0506580102Google Scholar
Swedish Schizophrenia Consortium, McClay, J. L., Shabalin, A. A., Dozmorov, M. G., Adkins, D. E., Kumar, G., … van den Oord, E. J. C. G. (2015). High density methylation QTL analysis in human blood via next-generation sequencing of the methylated genomic DNA fraction. Genome Biology, 16. doi:10.1186/s13059-015-0842-7Google Scholar
Szyf, M. (2012). How do environments talk to genes? Nature Neuroscience, 16, 2–4. doi:10.1038/nn.3286Google Scholar
Tobi, E. W., Lumey, L. H., Talens, R. P., Kremer, D., Putter, H., Stein, A. D., … Heijmans, B. T. (2009). DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Human Molecular Genetics, 18, 4046–4053. doi:10.1093/hmg/ddp353Google Scholar
Tsai, P.-C., & Bell, J. T. (2015). Power and sample size estimation for epigenome-wide association scans to detect differential DNA methylation. International Journal of Epidemiology, 44, 1429–1441. doi:10.1093/ije/dyv041Google Scholar
Turecki, G., & Meaney, M. J. (2016). Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Biological Psychiatry, 79, 87–96. doi:10.1016/j.biopsych.2014.11.022Google Scholar
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., … Meaney, M. J. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847–854. doi:10.1038/nn1276Google Scholar
Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A., … Kaufman, J. (2014). Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 417–424. doi:10.1016/j.jaac.2013.12.025Google Scholar
Zhu, M., & Zhao, S. (2007). Candidate gene identification approach: Progress and challenges. International Journal of Biological Sciences, 3, 420–427.Google Scholar