Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: Findings from the ENIGMA Epigenetics Working Group

Tianye Jia; Congying Chu; Yun Liu; Jenny van Dongen; Nicola J. Armstrong; Mark E. Bastin; Tania Carrillo-Roa; Anouk den Braber; Mathew Harris; Rick Jansen; Jingyu Liu; Michelle Luciano; Anil P.S. Ori; Roberto Roiz Santiañez; Barbara Ruggeri; Daniil Sarkisyan; Jean Shin; Kim Sungeun; Diana Tordesillas Gutiérrez; Dennis van't Ent; David Ames; Eric Artiges; Georgy Bakalkin; Tobias Banaschewski; Arun L.W. Bokde; Henry Brodaty; Uli Bromberg; Rachel Brouwer; Christian Büchel; Erin Burke Quinlan; Wiepke Cahn; Greig I. de Zubicaray; Tomas J. Ekström; Herta Flor; Juliane H. Fröhner; Vincent Frouin; Hugh Garavan; Penny Gowland; Andreas Heinz; Bernd Ittermann; Neda Jahanshad; Jiyang Jiang; John B. Kwok; Nicholas G. Martin; Jean Luc Martinot; Karen A. Mather; Katie L. McMahon; Allan F. McRae; Frauke Nees; Dimitri Papadopoulos Orfanos; Tomáš Paus; Luise Poustka; Philipp G. Sämann; Peter R. Schofield; Michael N. Smolka; Lachlan T. Strike; Jalmar Teeuw; Anbupalam Thalamuthu; Julian Trollor; Henrik Walter; Joanna M. Wardlaw; Wei Wen; Robert Whelan; Liana G. Apostolova; Elisabeth B. Binder; Dorret I. Boomsma; Vince Calhoun; Benedicto Crespo-Facorro; Ian J. Deary; Hilleke Hulshoff Pol; Roel A. Ophoff; Zdenka Pausova; Perminder S. Sachdev; Andrew Saykin; Margaret J. Wright; Paul M. Thompson; Gunter Schumann; Sylvane Desrivières

doi:10.1101/460444

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: Findings from the ENIGMA Epigenetics Working Group

Tianye Jia, Congying Chu, Yun Liu, Jenny van Dongen, Nicola J. Armstrong, Mark E. Bastin, Tania Carrillo-Roa, Anouk den Braber, Mathew Harris, Rick Jansen, Jingyu Liu, Michelle Luciano, Anil P.S. Ori, Roberto Roiz Santiañez, Barbara Ruggeri, Daniil Sarkisyan, Jean Shin, Kim Sungeun, Diana Tordesillas Gutiérrez, Dennis van't EntDavid Ames, Eric Artiges, Georgy Bakalkin, Tobias Banaschewski, Arun L.W. Bokde, Henry Brodaty, Uli Bromberg, Rachel Brouwer, Christian Büchel, Erin Burke Quinlan, Wiepke Cahn, Greig I. de Zubicaray, Tomas J. Ekström, Herta Flor, Juliane H. Fröhner, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Neda Jahanshad, Jiyang Jiang, John B. Kwok, Nicholas G. Martin, Jean Luc Martinot, Karen A. Mather, Katie L. McMahon, Allan F. McRae, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Philipp G. Sämann, Peter R. Schofield, Michael N. Smolka, Lachlan T. Strike, Jalmar Teeuw, Anbupalam Thalamuthu, Julian Trollor, Henrik Walter, Joanna M. Wardlaw, Wei Wen, Robert Whelan, Liana G. Apostolova, Elisabeth B. Binder, Dorret I. Boomsma, Vince Calhoun, Benedicto Crespo-Facorro, Ian J. Deary, Hilleke Hulshoff Pol, Roel A. Ophoff, Zdenka Pausova, Perminder S. Sachdev, Andrew Saykin, Margaret J. Wright, Paul M. Thompson, Gunter Schumann, Sylvane Desrivières

Research output: Contribution to journal › Article › peer-review

Abstract

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) -three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/460444
State	Published - Nov 5 2018
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences
General Immunology and Microbiology
General Neuroscience
Pharmacology, Toxicology and Pharmaceutics(all)

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10.1101/460444

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Jia, T., Chu, C., Liu, Y., van Dongen, J., Armstrong, N. J., Bastin, M. E., Carrillo-Roa, T., den Braber, A., Harris, M., Jansen, R., Liu, J., Luciano, M., Ori, A. P. S., Santiañez, R. R., Ruggeri, B., Sarkisyan, D., Shin, J., Sungeun, K., Gutiérrez, D. T., ... Desrivières, S. (2018). Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: Findings from the ENIGMA Epigenetics Working Group. Unknown Journal. https://doi.org/10.1101/460444

Jia, T, Chu, C, Liu, Y, van Dongen, J, Armstrong, NJ, Bastin, ME, Carrillo-Roa, T, den Braber, A, Harris, M, Jansen, R, Liu, J, Luciano, M, Ori, APS, Santiañez, RR, Ruggeri, B, Sarkisyan, D, Shin, J, Sungeun, K, Gutiérrez, DT, van't Ent, D, Ames, D, Artiges, E, Bakalkin, G, Banaschewski, T, Bokde, ALW, Brodaty, H, Bromberg, U, Brouwer, R, Büchel, C, Quinlan, EB, Cahn, W, de Zubicaray, GI, Ekström, TJ, Flor, H, Fröhner, JH, Frouin, V, Garavan, H, Gowland, P, Heinz, A, Ittermann, B, Jahanshad, N, Jiang, J, Kwok, JB, Martin, NG, Martinot, JL, Mather, KA, McMahon, KL, McRae, AF, Nees, F, Orfanos, DP, Paus, T, Poustka, L, Sämann, PG, Schofield, PR, Smolka, MN, Strike, LT, Teeuw, J, Thalamuthu, A, Trollor, J, Walter, H, Wardlaw, JM, Wen, W, Whelan, R, Apostolova, LG, Binder, EB, Boomsma, DI, Calhoun, V, Crespo-Facorro, B, Deary, IJ, Pol, HH, Ophoff, RA, Pausova, Z, Sachdev, PS, Saykin, A, Wright, MJ, Thompson, PM, Schumann, G & Desrivières, S 2018, 'Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: Findings from the ENIGMA Epigenetics Working Group', Unknown Journal. https://doi.org/10.1101/460444

@article{1300cc1476e748d6a4d2af7ec80c8ad9,

title = "Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: Findings from the ENIGMA Epigenetics Working Group",

abstract = "DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) -three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.",

author = "Tianye Jia and Congying Chu and Yun Liu and {van Dongen}, Jenny and Armstrong, {Nicola J.} and Bastin, {Mark E.} and Tania Carrillo-Roa and {den Braber}, Anouk and Mathew Harris and Rick Jansen and Jingyu Liu and Michelle Luciano and Ori, {Anil P.S.} and Santia{\~n}ez, {Roberto Roiz} and Barbara Ruggeri and Daniil Sarkisyan and Jean Shin and Kim Sungeun and Guti{\'e}rrez, {Diana Tordesillas} and {van't Ent}, Dennis and David Ames and Eric Artiges and Georgy Bakalkin and Tobias Banaschewski and Bokde, {Arun L.W.} and Henry Brodaty and Uli Bromberg and Rachel Brouwer and Christian B{\"u}chel and Quinlan, {Erin Burke} and Wiepke Cahn and {de Zubicaray}, {Greig I.} and Ekstr{\"o}m, {Tomas J.} and Herta Flor and Fr{\"o}hner, {Juliane H.} and Vincent Frouin and Hugh Garavan and Penny Gowland and Andreas Heinz and Bernd Ittermann and Neda Jahanshad and Jiyang Jiang and Kwok, {John B.} and Martin, {Nicholas G.} and Martinot, {Jean Luc} and Mather, {Karen A.} and McMahon, {Katie L.} and McRae, {Allan F.} and Frauke Nees and Orfanos, {Dimitri Papadopoulos} and Tom{\'a}{\v s} Paus and Luise Poustka and S{\"a}mann, {Philipp G.} and Schofield, {Peter R.} and Smolka, {Michael N.} and Strike, {Lachlan T.} and Jalmar Teeuw and Anbupalam Thalamuthu and Julian Trollor and Henrik Walter and Wardlaw, {Joanna M.} and Wei Wen and Robert Whelan and Apostolova, {Liana G.} and Binder, {Elisabeth B.} and Boomsma, {Dorret I.} and Vince Calhoun and Benedicto Crespo-Facorro and Deary, {Ian J.} and Pol, {Hilleke Hulshoff} and Ophoff, {Roel A.} and Zdenka Pausova and Sachdev, {Perminder S.} and Andrew Saykin and Wright, {Margaret J.} and Thompson, {Paul M.} and Gunter Schumann and Sylvane Desrivi{\`e}res",

note = "Publisher Copyright: 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-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2018",

month = nov,

day = "5",

doi = "10.1101/460444",

language = "English (US)",

journal = "Unknown Journal",

issn = "0309-1708",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes

T2 - Findings from the ENIGMA Epigenetics Working Group

AU - Jia, Tianye

AU - Chu, Congying

AU - Liu, Yun

AU - van Dongen, Jenny

AU - Armstrong, Nicola J.

AU - Bastin, Mark E.

AU - Carrillo-Roa, Tania

AU - den Braber, Anouk

AU - Harris, Mathew

AU - Jansen, Rick

AU - Liu, Jingyu

AU - Luciano, Michelle

AU - Ori, Anil P.S.

AU - Santiañez, Roberto Roiz

AU - Ruggeri, Barbara

AU - Sarkisyan, Daniil

AU - Shin, Jean

AU - Sungeun, Kim

AU - Gutiérrez, Diana Tordesillas

AU - van't Ent, Dennis

AU - Ames, David

AU - Artiges, Eric

AU - Bakalkin, Georgy

AU - Banaschewski, Tobias

AU - Bokde, Arun L.W.

AU - Brodaty, Henry

AU - Bromberg, Uli

AU - Brouwer, Rachel

AU - Büchel, Christian

AU - Quinlan, Erin Burke

AU - Cahn, Wiepke

AU - de Zubicaray, Greig I.

AU - Ekström, Tomas J.

AU - Flor, Herta

AU - Fröhner, Juliane H.

AU - Frouin, Vincent

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Ittermann, Bernd

AU - Jahanshad, Neda

AU - Jiang, Jiyang

AU - Kwok, John B.

AU - Martin, Nicholas G.

AU - Martinot, Jean Luc

AU - Mather, Karen A.

AU - McMahon, Katie L.

AU - McRae, Allan F.

AU - Nees, Frauke

AU - Orfanos, Dimitri Papadopoulos

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Sämann, Philipp G.

AU - Schofield, Peter R.

AU - Smolka, Michael N.

AU - Strike, Lachlan T.

AU - Teeuw, Jalmar

AU - Thalamuthu, Anbupalam

AU - Trollor, Julian

AU - Walter, Henrik

AU - Wardlaw, Joanna M.

AU - Wen, Wei

AU - Whelan, Robert

AU - Apostolova, Liana G.

AU - Binder, Elisabeth B.

AU - Boomsma, Dorret I.

AU - Calhoun, Vince

AU - Crespo-Facorro, Benedicto

AU - Deary, Ian J.

AU - Pol, Hilleke Hulshoff

AU - Ophoff, Roel A.

AU - Pausova, Zdenka

AU - Sachdev, Perminder S.

AU - Saykin, Andrew

AU - Wright, Margaret J.

AU - Thompson, Paul M.

AU - Schumann, Gunter

AU - Desrivières, Sylvane

N1 - Publisher Copyright: 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-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2018/11/5

Y1 - 2018/11/5

N2 - DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) -three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

AB - DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) -three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

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U2 - 10.1101/460444

DO - 10.1101/460444

M3 - Article

AN - SCOPUS:85095630714

SN - 0309-1708

JO - Unknown Journal

JF - Unknown Journal

ER -

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: Findings from the ENIGMA Epigenetics Working Group

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