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Original Investigation |

Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study

Carolina Montano, BS1,2; Margaret A. Taub, PhD3; Andrew Jaffe, PhD4,5; Eirikur Briem, MS2; Jason I. Feinberg, BS2; Rakel Trygvadottir, BS2; Adrian Idrizi, BS2; Arni Runarsson, BS2; Birna Berndsen, MS2; Ruben C. Gur, PhD6; Tyler M. Moore, PhD6; Rodney T. Perry, PhD7; Doug Fugman, PhD8; Sarven Sabunciyan, PhD9 ; Robert H. Yolken, MD9 ; Thomas M. Hyde, MD, PhD4; Joel E. Kleinman, MD, PhD4; Janet L. Sobell, PhD10; Carlos N. Pato, MD, PhD10; Michele T. Pato, MD10; Rodney C. Go, PhD7; Vishwajit Nimgaonkar, MD, PhD11; Daniel R. Weinberger, MD4; David Braff, MD12,13; Raquel E. Gur, MD, PhD6; Margaret Daniele Fallin, PhD2,5; Andrew P. Feinberg, MD, MPH2,5,14
[+] Author Affiliations
1Medical Scientist Training Program and Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland
2Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland
3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
4Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
5Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
6Neuropsychiatry Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
7Department of Epidemiology, University of Alabama at Birmingham, Birmingham
8Rutgers University Cell and DNA Repository, Piscataway, New Jersey
9 Stanley Division of Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, Maryland
10Department of Psychiatry and Behavioral Sciences, Keck School of Medicine of University of Southern California, Los Angeles
11Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
12Department of Psychiatry, University of California San Diego School of Medicine, La Jolla
13VISN22, Mental Illness Research, Education, and Clinical Center, VA Veterans Affairs San Diego Healthcare System, San Diego, California
14Departments of Medicine and Biomedical Engineering, Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, Maryland
JAMA Psychiatry. 2016;73(5):506-514. doi:10.1001/jamapsychiatry.2016.0144.
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Importance  DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk.

Objective  To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls.

Design, Setting, and Participants  Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort.

Main Outcomes and Measures  Identification of differentially methylated positions across the genome in SZ cases compared with controls.

Results  Of the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non–African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non–African American. In our replication set, cases/controls were 76% male and 100% non–African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses.

Conclusions and Relevance  This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.

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Figure 1.
Analysis Workflow

Filtering steps and statistical design.

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Figure 2.
Changes in DNA Methylation are Concordant Between Discovery and Replication Data Sets

A, Regression coefficients of the DNA methylation differences at the top-ranked 150 differentially methylated positions in the discovery set are significantly correlated with the coefficients found in the replication set (r = 0.63; P value <.001). B, DNA methylation for an individual CpG in the intron of NCOR2, in the discovery (top) and replication (bottom) data sets, and corresponding P values for neighboring CpGs.

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Figure 3.
Genotype-Dependent Differentially Methylated Positions in Psychiatric Genomics Consortium Schizophrenia-Associated Locus

A, Psychiatric Genomics Consortium Genome-Wide Association Study locus (region 11) with an overlapping schizophrenia (SZ)-associated CpG. Dashed lines indicate single-nucleotide polymorphism–CpG cisregulation between the 2 SZ–single-nucleotide polymorphisms and locus cg25647583. B, Methylation differences between SZ cases and controls at locus cg25647583. C, Association between DNA methylation and genotype. In the Psychiatric Genomics Consortium Genome-Wide Association Study , the A allele is the risk allele (odds ratio = 1.0662). D, Association between genotype and SZ phenotype. The risk allele has increased frequency in our SZ cases. E, β coefficient estimate of the dependence of genotype on SZ phenotype, before and after adjusting for methylation. Error bars represent the 95% CIs for the estimate of β.

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