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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)...


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.


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:


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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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