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Stress exposure and psychopathology alter methylation of the serotonin receptor 2A (HTR2A) gene in preschoolers

  • Stephanie H. Parade (a1) (a2), Andrew M. Novick (a1) (a3), Justin Parent (a1) (a2) (a4), Ronald Seifer (a1) (a2), Samantha J. Klaver (a2), Carmen J. Marsit (a5), Asi Polly Gobin (a3), Bao-Zhu Yang (a6) and Audrey R. Tyrka (a1) (a3)...

Abstract

Serotonin signaling pathways play a key role in brain development, stress reactivity, and mental health. Epigenetic alterations in the serotonin system may underlie the effect of early life stress on psychopathology. The current study examined methylation of the serotonin receptor 2A (HTR2A) gene in a sample of 228 children including 119 with child welfare documentation of moderate to severe maltreatment within the last 6 months. Child protection records, semistructured interviews in the home, and parent reports were used to assess child stress exposure, psychiatric symptoms, and behavior. The HTR2A genotype and methylation of HTR2A were measured at two CpG sites (–1420 and –1224) from saliva DNA. HTR2A genotype was associated with HTR2A methylation at both CpG sites. HTR2A genotype also moderated associations of contextual stress exposure and HTR2A methylation at site –1420. Contextual stress was positively associated with –1420 methylation among A homozygotes, but negatively associated with –1420 methylation among G homozygotes. Posttraumatic stress disorder and major depressive disorder symptoms were negatively associated with methylation at –1420, but positively associated with methylation at –1224. Results support the view that the serotonin system is sensitive to stress exposure and psychopathology, and HTR2A methylation may be a mechanism by which early adversity is biologically encoded.

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Corresponding author

Address correspondence and reprint requests to: Stephanie H. Parade, Bradley Research Center, E. P. Bradley Hospital, 1011 Veterans Memorial Parkway, East Providence, RI 02915; E-mail: Stephanie_Parade@Brown.edu.

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This research was supported by Grant R01 MH083704 (to A.R.T.) and R25 MH101076 (A.M.N.) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIMH. We are grateful to the children and families who participated in this study, and we thank Hasbro Children's Hospital, Rhode Island Head Start, and the Rhode Island Department of Children, Youth, and Families for assisting in recruitment of study participants. We also thank Brittney Josefson and the numerous other research assistants who contributed to this project. Isolation of DNA and the genotyping array were done in the laboratory of Joel Gelernter, MD, and we are grateful to Dr. Gelernter and his staff for their contribution.

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References

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Abdolmaleky, H. M., Yaqubi, S., Papageorgis, P., Lambert, A. W., Ozturk, S., Sivaraman, V., & Thiagalingam, S. (2011). Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophrenia Research, 129, 183190. doi:10.1016/j.schres.2011.04.007
Achenbach, T. M., & Rescorla, L. A. (2000). Manual for the ASEBA preschool forms & profiles: An integrated system of multi-informant assessment. Burlington, VT: University of Vermont, Department of Psychiatry.
Amidfar, M., Kim, Y.-K., Colic, L., Arbabi, M., Mobaraki, G., Hassanzadeh, G., & Walter, M. (2017). Increased levels of 5HT2A receptor mRNA expression in peripheral blood mononuclear cells of patients with major depression: Correlations with severity and duration of illness. Nordic Journal of Psychiatry, 71, 282288. doi:10.1080/08039488.2016.1276624
Arnsten, A. F. T. (2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience, 10, 410422. doi:10.1038/nrn2648
Azmitia, E. C. (2001). Modern views on an ancient chemical: Serotonin effects on cell proliferation, maturation, and apoptosis. Brain Research Bulletin, 56, 413424. doi:10.1016/S0361-9230(01)00614-1
Aznar, S., & Klein, A. B. (2013). Regulating prefrontal cortex activation: An emerging role for the 5-HT2A serotonin receptor in the modulation of emotion-based actions? Molecular Neurobiology, 48, 841853. doi:10.1007/s12035-013-8472
Barnett, D., Manly, J. T., & Cicchetti, D. (1993). Defining child maltreatment: The interface between policy and research. In Cicchetti, D. & Toth, S. L. (Eds.), Child abuse, child development, and social policy (pp. 773). Norwood, NJ: Ablex.
Benjet, C., Borges, G., & Medina-Mora, M. E. (2010). Chronic childhood adversity and onset of psychopathology during three life stages: Childhood, adolescence and adulthood. Journal of Psychiatric Research, 44, 732740. doi:10.1016/j.jpsychires.2010.01.004
Bonnier, B., Gorwood, P., Hamon, M., Sarfati, Y., Boni, C., & Hardy-Bayle, M.-C. (2002). Association of 5-HT(2A) receptor gene polymorphism with major affective disorders: The case of a subgroup of bipolar disorder with low suicide risk. Biological Psychiatry, 51, 762765. doi:10.1016/S0006-3223(01)01228-8
Booij, L., Tremblay, R., Szyf, M., & Benkelfat, C. (2015). Genetic and early environmental influences on the serotonin system: Consequences for brain development and risk for psychopathology. Journal of Psychiatry & Neuroscience, 40, 518. doi:10.1503/jpn.140099
Bray, N. J., Buckland, P. R., Hall, H., Owen, M. J., & O'Donovan, M. C. (2004). The serotonin 2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain. Molecular Psychiatry, 9, 109114. doi:10.1038/sj.mp.4001366
Bufferd, S. J., Dougherty, L. R., Carlson, G. A., & Klein, D. N. (2011). Parent-reported mental health in preschoolers: Findings using a diagnostic interview. Comprehensive Psychiatry, 52, 359369. doi:10.1016/j.comppsych.2010.08.006
Cohen, S., Janicki-Deverts, D., & Miller, G. E. (2007). Psychological stress and disease. Journal of the American Medical Association, 298, 16851687. doi:10.1001/jama.298.14.1685
Conradt, E. (2017). Using principles of behavioral epigenetics to advance research on early life stress. Child Development Perspectives, 11, 107112. doi:10.1111/cdep.12219
Duman, E. A., & Canli, T. (2015). Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males. Biology of Mood & Anxiety Disorders, 5, 2. doi:10.1186/s13587-015-0017
Dwivedi, Y., Mondal, A. C., Payappagoudar, G. V., & Rizavi, H. S. (2005). Differential regulation of serotonin (5HT)2A receptor mRNA and protein levels after single and repeated stress in rat brain: Role in learned helplessness behavior. Neuropharmacology, 48, 204214. doi:10.1016/j.neuropharm.2004.10.004
Egger, G., Liang, G., Aparicio, A., & Jones, P. A. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429, 457463. doi:10.1038/nature02625
Ellingrod, V. L., Lund, B. C., Miller, D., Fleming, F., Perry, P., Holman, T. L., & Bever-Stille, K. (2003). 5-HT2A receptor promoter polymorphism, –1438G/A and negative symptom response to olanzapine in schizophrenia. Psychopharmacology Bulletin, 37, 109112.
Enoch, M. A., Goldman, D., Barnett, R., Sher, L., Mazzanti, C. M., & Rosenthal, N. E. (1999). Association between seasonal affective disorder and the 5-HT2A promoter polymorphism, –1438G/A. Molecular Psychiatry, 4, 8992. doi:10.1038/sj.mp.4000439
Falkenberg, V. R., Gurbaxani, B. M., Unger, E. R., & Rajeevan, M. S. (2011). Functional genomics of serotonin receptor 2A (HTR2A): Interaction of polymorphism, methylation, expression and disease association. Neuromolecular Medicine, 13, 6676. doi:10.1007/s12017-010-8138-2
Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., … Marks, J. S. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The Adverse Childhood Experiences (ACE) Study. American Journal of Preventive Medicine, 14, 245258. doi:10.1016/S0749-3797(98)00017-8
Frank, G. K., Kaye, W. H., Meltzer, C. C., Price, J. C., Greer, P., McConaha, C., & Skovira, K. (2002). Reduced 5-HT2A receptor binding after recovery from anorexia nervosa. Biological Psychiatry, 52, 896906. doi:10.1016/S0006-3223(02)01378-1
Ghadirivasfi, M., Nohesara, S., Ahmadkhaniha, H.-R., Eskandari, M.-R., Mostafavi, S., Thiagalingam, S., & Abdolmaleky, H. M. (2011). Hypomethylation of the serotonin receptor type-2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder. American Journal of Medical Genetics, 156B, 536545. doi:10.1002/ajmg.b.31192
González-Maeso, J., & Sealfon, S. C. (2009). Psychedelics and schizophrenia. Trends in Neurosciences, 32, 225232. doi:10.1016/j.tins.2008.12.005
González-Maeso, J., Weisstaub, N. V., Zhou, M., Chan, P., Ivic, L., Ang, R., … Gingrich, J. A. (2007). Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron, 53, 439452. doi:10.1016/j.neuron.2007.01.008
Graeff, F. G., Viana, M. B., & Mora, P. O. (1997). Dual role of 5-HT in defense and anxiety. Neuroscience and Biobehavioral Reviews, 21, 791799. doi:10.1016/S0149-7634(96)00059-0
Hernandez, I., & Sokolov, B. P. (2000). Abnormalities in 5-HT2A receptor mRNA expression in frontal cortex of chronic elderly schizophrenics with varying histories of neuroleptic treatment. Journal of Neuroscience Research, 59, 218225. doi:10.1002/(SICI)1097-4547(20000115)59:2<218::AID-JNR8>3.0.CO;2-H
Holloway, T., & González-Maeso, J. (2015). Epigenetic mechanisms of serotonin signaling. ACS Chemical Neuroscience, 6, 10991109. doi:10.1021/acschemneuro.5b00033
Hurlemann, R., Matusch, A., Kuhn, K.-U., Berning, J., Elmenhorst, D., Winz, O., … Bauer, A. (2007). 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology, 195, 579590. doi:10.1007/s00213-007-0921-x
Jin, C., Xu, W., Yuan, J., Wang, G., & Cheng, Z. (2013). Meta-analysis of association between the –1438A/G (rs6311) polymorphism of the serotonin 2A receptor gene and major depressive disorder. Neurological Research, 35, 714. doi:10.1179/1743132812Y.0000000111
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68, 444. doi:10.1001/archgenpsychiatry.2010.189
Kato, M., & Serretti, A. (2010). Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry, 15, 473500. doi:10.1038/mp.2008.116
Lee, H.-J., Sung, S.-M., Lim, S.-W., Paik, J.-W., & Kim, L. (2006). Seasonality associated with the serotonin 2A receptor –1438 A/G polymorphism. Journal of Affective Disorders, 95, 145148. doi:10.1016/j.jad.2006.05.001
Lin, S. H., Lee, L. T., & Yang, Y. K. (2014). Serotonin and mental disorders: A concise review on molecular neuroimaging evidence. Clinical Psychopharmacology and Neuroscience, 12, 196. doi:10.9758/cpn.2014.12.3.196
Little, R. J. (1988). A test of missing completely at random for multivariate data with missing values. Journal of the American Statistical Association, 83, 11981202. doi:10.2307/2290157
Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38, 2338. doi:10.1038/npp.2012.112
Paquette, A. G., Lesseur, C., Armstrong, D. A., Koestler, D. C., Appleton, A. A., Lester, B. M., & Marsit, C. J. (2013). Placental HTR2A methylation is associated with infant neurobehavioral outcomes. Epigenetics, 8, 796801. doi:10.4161/epi.25358
Paquette, A. G., & Marsit, C. J. (2014). The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. Journal of Cellular Biochemistry, 115, 20652072. doi:10.1002/jcb.24883
Parsons, M. J., D'Souza, U. M., Arranz, M.-J., Kerwin, R. W., & Makoff, A. J. (2004). The –1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biological Psychiatry, 56, 406410. doi:10.1016/j.biopsych.2004.06.020
Peters, D. A. (1988). Both prenatal and postnatal factors contribute to the effects of maternal stress on offspring behavior and central 5-hydroxytryptamine receptors in the rat. Pharmacology Biochemistry and Behavior, 30, 669673. doi:10.1016/0091-3057(88)90081-0
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics, 38, 904909. doi:10.1038/ng1847
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., … Sham, P. C. (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559575.
Reik, W. (2007). Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 447, 425432. doi:10.1038/nature05918
Rentesi, G., Antoniou, K., Marselos, M., Syrrou, M., Papadopoulou-Daifoti, Z., & Konstandi, M. (2013). Early maternal deprivation-induced modifications in the neurobiological, neurochemical and behavioral profile of adult rats. Behavioural Brain Research, 244, 2937. doi:10.1016/j.bbr.2013.01.040
Scheeringa, M. S., & Haslett, N. (2010). The reliability and criterion validity of the Diagnostic Infant and Preschool Assessment: A new diagnostic instrument for young children. Child Psychiatry & Human Development, 41, 299312. doi:10.1007/s10578-009-0169-2
Selvaraj, S., Arnone, D., Cappai, A., & Howes, O. (2014). Alterations in the serotonin system in schizophrenia: A systematic review and meta-analysis of postmortem and molecular imaging studies. Neuroscience & Biobehavioral Reviews, 45, 233245. doi:10.1016/j.neubiorev.2014.06.005
Serretti, A., Drago, A., & De Ronchi, D. (2007). HTR2A gene variants and psychiatric disorders: A review of current literature and selection of SNPs for future studies. Current Medicinal Chemistry, 14, 20532069. doi:10.2174/092986707781368450
Smith, R. M., Papp, A. C., Webb, A., Ruble, C. L., Munsie, L. M., Nisenbaum, L. K., … Sadee, W. (2013). Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex. Biological Psychiatry, 73, 546554. doi:10.1016/j.biopsych.2012.09.028
Soloff, P. H., Price, J. C., Meltzer, C. C., Fabio, A., Frank, G. K., & Kaye, W. H. (2007). 5HT2A receptor binding is increased in borderline personality disorder. Biological Psychiatry, 62, 580587. doi:10.1016/j.biopsych.2006.10.022
Stockmeier, C. A. (2003). Involvement of serotonin in depression: Evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. Journal of Psychiatric Research, 37, 357373. doi:10.1016/S0022-3956(03)00050-5
Szyf, M. (2007). The dynamic epigenome and its implications in toxicology. Toxicological Sciences, 100, 723. doi:10.1093/toxsci/kfm177
Szyf, M. (2013). DNA methylation, behavior and early life adversity. Journal of Genetics and Genomics, 40, 331338.
Turecki, G., Brière, R., Dewar, K., Antonetti, T., Lesage, A. D., Séguin, M., … Benkelfat, C. (1999). Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. American Journal of Psychiatry, 156, 14561458. doi:10.1176/ajp.156.9.1456
Uddin, M., Koenen, K. C., Aiello, A. E., Wildman, D. E., de Los Santos, R., & Galea, S. (2011). Epigenetic and inflammatory marker profiles associated with depression in a community based epidemiologic sample. Psychological Medicine, 41, 997. doi:10.1017/S0033291710001674
Zangrossi, H., Viana, M. B., Zanoveli, J., Bueno, C., Nogueira, R. L., & Graeff, F. G. (2001). Serotonergic regulation of inhibitory avoidance and one-way escape in the rat elevated T-maze. Neuroscience & Biobehavioral Reviews, 25, 637645. doi:10.1016/S0149-7634(01)00047-1
Zhao, X., Sun, L., Sun, Y.-H., Ren, C., Chen, J., Wu, Z.-Q., … Lv, X.-L. (2014). Association of HTR2A T102C and A–1438G polymorphisms with susceptibility to major depressive disorder: A meta-analysis. Neurological Sciences, 35, 18571866. doi:10.1007/s10072-014-1970-7
Zhu, Q. S., Chen, K., & Shih, J. C. (1995). Characterization of the human 5-HT2A receptor gene promoter. Journal of Neuroscience, 15, 48854895.

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