TY - JOUR
T1 - Association of DNA methylation differences with schizophrenia in an epigenome-wide association study
AU - Montano, Carolina
AU - Taub, Margaret A.
AU - Jaffe, Andrew
AU - Briem, Eirikur
AU - Feinberg, Jason I.
AU - Trygvadottir, Rakel
AU - Idrizi, Adrian
AU - Runarsson, Arni
AU - Berndsen, Birna
AU - Gur, Ruben C.
AU - Moore, Tyler M.
AU - Perry, Rodney T.
AU - Fugman, Doug
AU - Sabunciyan, Sarven
AU - Yolken, Robert H.
AU - Hyde, Thomas M.
AU - Kleinman, Joel E.
AU - Sobell, Janet L.
AU - Pato, Carlos N.
AU - Pato, Michele T.
AU - Go, Rodney C.
AU - Nimgaonkar, Vishwajit
AU - Weinberger, Daniel R.
AU - Braff, David
AU - Gur, Raquel E.
AU - Fallin, Margaret Daniele
AU - Feinberg, Andrew P.
N1 - Publisher Copyright:
© 2016 American Medical Association. All rights reserved.
PY - 2016/5
Y1 - 2016/5
N2 - Importance: DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. O. 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.
AB - Importance: DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. O. 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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U2 - 10.1001/jamapsychiatry.2016.0144
DO - 10.1001/jamapsychiatry.2016.0144
M3 - Article
C2 - 27074206
AN - SCOPUS:84973279140
SN - 2168-622X
VL - 73
SP - 506
EP - 514
JO - JAMA psychiatry
JF - JAMA psychiatry
IS - 5
ER -