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

Marco P Boks ,Hilleke E Hulshoff Pol ,Dewleen G Baker ,Lotte C Houtepen ,Andrew E Jaffe ,Elly M Hol ,Bart P F Rutten ,Ying Wu ,Daniel R Weinberger ,Yujie He ,Christiaan H Vinkers ,Qiong Yu ,Hao Xu ,Joel E Kleinman ,Prashanth Rajarajan ,Schahram Akbarian ,Lot De Witte ,Adam X Maihofer ,Gianluca Ursini ,Zhida Xu ,Caroline M Nievergelt ,S Wang ,Jieping Shi ,Jinghai Yu ,Eric Strengman ,René S Kahn

doi:10.1038/s41537-018-0058-4

Abstract

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.

Highlights

Schizophrenia is a severe psychiatric disorder with a global lifetime risk of around 1% and a typical onset in late adolescence and early adulthood
The genome-wide methylation analysis of the Chinese famine sample identified one single region containing the dual specificity phosphatase 22 (DUSP22) gene promoter with higher DNA methylation levels in the famine-exposed schizophrenia patients compared to all other groups (Chr6: 291687-293285, Family Wise Error Rate (FWER) = 0.01)
DUSP22 methylation was higher in postmortem prefrontal cortex (PFC) tissue of schizophrenia patients (N = 91; mean methylation = 0.40, sd = 0.10) compared to unaffected controls (N = 123; mean methylation = 0.37, sd = 0.13) (B = 0.35, p = 0.007)

Summary

Introduction

Schizophrenia is a severe psychiatric disorder with a global lifetime risk of around 1% and a typical onset in late adolescence and early adulthood. We hypothesized that changes in DNA methylation play a role in the increased risk to develop schizophrenia after in utero exposure to famine. To test this hypothesis, we focused on the great famine in China between 1959 and 1961, which led to an estimated death toll of over 30 million.[12] The high penetrance of famine in a large rural population during a restricted period offers an opportunity for selective sampling of schizophrenia patients and healthy controls on the basis of their exposure to famine. We carried out in vitro experimental studies whereby human fibroblasts were exposed to nutritional deprivation to directly investigate methylation responses to nutritional deprivation without the potential confounds of genetic differences, medication, and other environmental factors

Methods

Results

Conclusion