TY - JOUR
T1 - Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
AU - Perzel Mandell, Kira A.
AU - Eagles, Nicholas J.
AU - Wilton, Richard
AU - Price, Amanda J.
AU - Semick, Stephen A.
AU - Collado-Torres, Leonardo
AU - Ulrich, William S.
AU - Tao, Ran
AU - Han, Shizhong
AU - Szalay, Alexander S.
AU - Hyde, Thomas M.
AU - Kleinman, Joel E.
AU - Weinberger, Daniel R.
AU - Jaffe, Andrew E.
N1 - Funding Information:
We would like to express their gratitude to our colleagues whose tireless efforts have led to the donation of postmortem tissue to advance these studies: the Office of the Chief Medical Examiner of the District of Columbia; the Office of the Chief Medical Examiner for Northern Virginia, Fairfax Virginia; and the Office of the Chief Medical Examiner of the State of Maryland, Baltimore, Maryland. We would also like to acknowledge Lle-wellyn B. Bigelow, MD, for his diagnostic expertise. This project was supported by The Lieber Institute for Brain Development and by NIH grants R01MH112751 and T32GM781437. Finally, we are indebted to the generosity of the families of the decedents, who donated the brain tissue used in these studies.
Funding Information:
We have created a user-friendly and fast meQTL browser that allows searching by SNPs or cytosines by genomic regions (chr.start-end) at https://eqtl.brainseq.org/WGBS_meQTL/. Raw and processed nucleic acid sequencing data generated to support the findings of this study are available via the PsychENCODE Knowledge Portal (https:// psychencode.synapse.org/). The PsychENCODE Knowledge Portal is a platform for accessing data, analyses, and tools generated through grants funded by the National Institute of Mental Health (NIMH) PsychENCODE program. Data is available for general research use according to the following requirements for data access and data attribution: (https://psychencode.synapse.org/DataAccess). For access to content described in this
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction. Using whole-genome bisulfite sequencing, we have surveyed DNAm in 344 samples of human postmortem brain tissue from neurotypical subjects and individuals with schizophrenia. We identify genetic influence on local methylation levels throughout the genome, both at CpG sites and CpH sites, with 86% of SNPs and 55% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting the genes and regions with which these loci are epigenetically associated. These findings can be used to better characterize schizophrenia GWAS-identified variants as epigenetic risk variants. Regions differentially methylated by schizophrenia risk-SNPs explain much of the heritability associated with risk loci, despite covering only a fraction of the genomic space. We provide a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain.
AB - DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction. Using whole-genome bisulfite sequencing, we have surveyed DNAm in 344 samples of human postmortem brain tissue from neurotypical subjects and individuals with schizophrenia. We identify genetic influence on local methylation levels throughout the genome, both at CpG sites and CpH sites, with 86% of SNPs and 55% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting the genes and regions with which these loci are epigenetically associated. These findings can be used to better characterize schizophrenia GWAS-identified variants as epigenetic risk variants. Regions differentially methylated by schizophrenia risk-SNPs explain much of the heritability associated with risk loci, despite covering only a fraction of the genomic space. We provide a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain.
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U2 - 10.1038/s41467-021-25517-3
DO - 10.1038/s41467-021-25517-3
M3 - Article
C2 - 34475392
AN - SCOPUS:85114647313
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5251
ER -