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NPJ Schizophr. 2018 Aug 21;4(1):16. doi: 10.1038/s41537-018-0058-4.

Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia.

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Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, USA.
Department of Psychiatry, University of California, La Jolla, San Diego, CA, USA.
VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA.
Department of Epidemiology and Health Statistics, School of Public Health, Jilin University, Changchun, China.
Molecular Pathology, Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.


Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently, we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation, we exposed human fibroblasts to nutritional deprivation. In the famine-exposed schizophrenia patients, we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N = 153, p = 0.01). In this sample, DUSP22 methylation was also significantly higher in patients independent of famine exposure (p = 0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control samples not exposed to famine using DNA from whole blood (N = 64, p = 0.03) and postmortem brains (N = 214, p = 0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p = 0.048) and expression (p = 0.019) in response to nutritional deprivation (N = 10). These results highlight an epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early-life exposure to famine and that is relevant for a major psychiatric disorder.

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