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Original Investigation |

Methylome-Wide Association Study of Schizophrenia:  Identifying Blood Biomarker Signatures of Environmental Insults

Karolina A. Aberg, PhD1; Joseph L. McClay, PhD1; Srilaxmi Nerella, MS1; Shaunna Clark, PhD1; Gaurav Kumar, PhD1; Wenan Chen, PhD2; Amit N. Khachane, PhD1; Linying Xie, MS1; Alexandra Hudson, BS1; Guimin Gao, PhD2; Aki Harada, PhD1; Christina M. Hultman, MD3; Patrick F. Sullivan, MD3,4; Patrik K. E. Magnusson, PhD3; Edwin J. C. G. van den Oord, PhD1
[+] Author Affiliations
1Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond
2Department of Biostatistics, Virginia Commonwealth University, Richmond
3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
4Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill
JAMA Psychiatry. 2014;71(3):255-264. doi:10.1001/jamapsychiatry.2013.3730.
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Importance  Epigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve disease management.

Objective  To identify schizophrenia DNA methylation biomarkers in blood.

Design, Setting, and Participants  The sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG–binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case-control participants using targeted pyrosequencing of bisulfite-converted DNA.

Main Outcomes and Measures  Status of schizophrenia cases and controls.

Results  Our MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 × 10−10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia.

Conclusions and Relevance  To our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management.

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Methylome-Wide Association Study Manhattan Plot

The 22 autosomes are displayed along the x-axis, with the negative logarithm of the association P value for each block displayed on the y-axis. All P values above the upper (red) line have q values of less than 0.01, and those above the lower (blue) line have q values of less than 0.1.

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