The relationship of childhood trauma and DNA methylation of NMDA receptor genes in first-episode schizophrenia

Abstract

Aim: We investigated GRIN1, GRIN2A, GRIN2B and LINE-1 DNA methylation in first-episode schizophrenia patients, their nonaffected siblings and age- and sex-matched controls testing for associations between DNA methylation and exposition to childhood trauma. Materials & methods: The Childhood Trauma Questionnaire evaluated the history of childhood trauma. Genomic DNA was bisulfite converted and pyrosequencing was employed to quantify DNA methylation. Results:GRIN2A, GRIN2B and LINE-1 DNA methylation was not associated with childhood trauma in patients, siblings and controls. Siblings with childhood trauma had hypermethylation at CpG1 of GRIN1 compared with siblings without trauma. Conclusion: Childhood trauma may influence GRIN1 methylation in subjects with liability to psychosis, but not in frank schizophrenia or controls.

Lay abstract

Schizophrenia results from a combination of genetic and environmental influences. We investigated how some changes in genes can be silenced by a process named DNA methylation and may be linked to schizophrenia. For this reason, we hypothesized that childhood trauma, an environmental risk factor, would be associated with DNA methylation in schizophrenia patients compared with their unaffected siblings and controls. Our research has shown that altered blood DNA methylation of one candidate gene for psychiatric disorders may be associated with childhood trauma in the unaffected siblings of schizophrenia patients, but not in frank schizophrenia or controls. We believe that this gene plays an important role in helping identify vulnerable as well as resilient individuals to schizophrenia disorder.

Keywords::

• childhood trauma
• DNA methylation
• first-episode schizophrenia
• GRIN1
• GRIN2A
• GRIN2B
• NMDAR genes
• siblings

Financial & competing interests disclosure

This study was supported by the research grant from the clinical research fund of Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) – Finance Code 001. Funding for this study was provided by the FAPESP (grants: 2012/05178-0 and 2013/08216-2). CM Loureiro is a recipient of a scholarship from CAPES. HA Fachim, F Corsi-Zuelli and R Shuhama are recipients of fellowships from FAPESP (grants: 2017/00624-5 and 2015/02948-7; 2019/13229-2 and 2016/12195-9; 2013/11167-3, respectively). PR Menezes (level 1B), CM Del-Ben (level 1B) and P Louzada-Junior (level 2) are recipients of fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). GP Reynolds has received honoraria for lectures and/or advisory panel membership from Kang Hong, Lundbeck, Otsuka and Sumitomo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.