0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
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.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Figures

Place holder to copy figure label and caption
Figure.
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.

Graphic Jump Location

Tables

References

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 5

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
brightcove.createExperiences();