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Widespread methylation quantitative trait loci and their role in schizophrenia risk

View ORCID ProfileKira A. Perzel Mandell, Nicholas J. Eagles, Richard Wilton, View ORCID ProfileAmanda J. Price, Stephen A. Semick, View ORCID ProfileLeonardo Collado-Torres, Ran Tao, Shizhong Han, Alexander S. Szalay, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, View ORCID ProfileAndrew E. Jaffe
doi: https://doi.org/10.1101/2020.09.24.311878
Kira A. Perzel Mandell
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
2Department of Genetic Medicine, Johns Hopkins University School of Medicine (JHSOM), Baltimore, MD 21205, USA
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  • ORCID record for Kira A. Perzel Mandell
Nicholas J. Eagles
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Richard Wilton
3Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD, USA
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Amanda J. Price
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
2Department of Genetic Medicine, Johns Hopkins University School of Medicine (JHSOM), Baltimore, MD 21205, USA
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Stephen A. Semick
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Leonardo Collado-Torres
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Ran Tao
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Shizhong Han
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
4Department of Psychiatry and Behavioral Sciences, JHSOM, Baltimore, MD, USA
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Alexander S. Szalay
3Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD, USA
5Department of Computer Science, JHSOM, Baltimore, MD, USA
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Thomas M. Hyde
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
4Department of Psychiatry and Behavioral Sciences, JHSOM, Baltimore, MD, USA
6Department of Neurology, JHSOM, Baltimore, MD, USA
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Joel E. Kleinman
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
4Department of Psychiatry and Behavioral Sciences, JHSOM, Baltimore, MD, USA
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Daniel R. Weinberger
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
2Department of Genetic Medicine, Johns Hopkins University School of Medicine (JHSOM), Baltimore, MD 21205, USA
4Department of Psychiatry and Behavioral Sciences, JHSOM, Baltimore, MD, USA
6Department of Neurology, JHSOM, Baltimore, MD, USA
7Department of Neuroscience, JHSOM, Baltimore, MD, USA
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Andrew E. Jaffe
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
2Department of Genetic Medicine, Johns Hopkins University School of Medicine (JHSOM), Baltimore, MD 21205, USA
4Department of Psychiatry and Behavioral Sciences, JHSOM, Baltimore, MD, USA
7Department of Neuroscience, JHSOM, Baltimore, MD, USA
8Department of Mental Health, Johns Hopkins Bloomberg School of Public Health (JHBSPH), MD 21205, USA
9Department of Biostatistics, JHBSPH, Baltimore, MD, USA
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  • ORCID record for Andrew E. Jaffe
  • For correspondence: andrew.jaffe@libd.org
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Abstract

DNA methylation (DNAm) regulates gene expression and may represent gene-environment interactions. Using whole genome bisulfite sequencing, we surveyed DNAm in a large sample (n=344) of human brain tissues. We identify widespread genetic influence on local methylation levels throughout the genome, with 76% of SNPs and 38% 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 putative functional regions that explain much of the heritability associated with risk loci. Furthermore, some CpH sites associated with genetic variation. We have established 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.

One-sentence summary Most genetic variants associated with DNA methylation levels, and implicated schizophrenia GWAS variants in the human brain.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 24, 2020.
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Widespread methylation quantitative trait loci and their role in schizophrenia risk
Kira A. Perzel Mandell, Nicholas J. Eagles, Richard Wilton, Amanda J. Price, Stephen A. Semick, Leonardo Collado-Torres, Ran Tao, Shizhong Han, Alexander S. Szalay, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, Andrew E. Jaffe
bioRxiv 2020.09.24.311878; doi: https://doi.org/10.1101/2020.09.24.311878
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Widespread methylation quantitative trait loci and their role in schizophrenia risk
Kira A. Perzel Mandell, Nicholas J. Eagles, Richard Wilton, Amanda J. Price, Stephen A. Semick, Leonardo Collado-Torres, Ran Tao, Shizhong Han, Alexander S. Szalay, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, Andrew E. Jaffe
bioRxiv 2020.09.24.311878; doi: https://doi.org/10.1101/2020.09.24.311878

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