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, Evangelos Papastergios, 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 & 62 others 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, Stefan Ehrlich, Tomas J Ekström, Herta Flor, Juliane H Fröhner, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Jacqueline Hoare, 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, Dan J Stein, 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, Dennis van t Ent, Sylvane Desrivières

Research output: Contribution to JournalArticleAcademicpeer-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 3337 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. 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 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 languageEnglish
JournalMolecular Psychiatry
DOIs
Publication statusE-pub ahead of print - 6 Dec 2019

Fingerprint

DNA Methylation
Epigenomics
Meta-Analysis
Nucleus Accumbens
Thalamus
Brain
Biomarkers
Gene Expression
DNA Fingerprinting
Environmental Exposure
Brain Diseases
Sample Size
Type 2 Diabetes Mellitus
Cluster Analysis
Cell Differentiation
Hippocampus
Fatty Acids
Stem Cells
Maintenance
Learning

Cite this

Jia, Tianye ; Chu, Congying ; Liu, Yun ; van Dongen, Jenny ; Papastergios, Evangelos ; Armstrong, Nicola J ; Bastin, Mark E ; Carrillo-Roa, Tania ; den Braber, Anouk ; Harris, Mathew ; Jansen, Rick ; Liu, Jingyu ; Luciano, Michelle ; Ori, Anil P S ; Roiz Santiañez, Roberto ; Ruggeri, Barbara ; Sarkisyan, Daniil ; Shin, Jean ; Sungeun, Kim ; Tordesillas Gutiérrez, Diana ; Ames, David ; Artiges, Eric ; Bakalkin, Georgy ; Banaschewski, Tobias ; Bokde, Arun L W ; Brodaty, Henry ; Bromberg, Uli ; Brouwer, Rachel ; Büchel, Christian ; Burke Quinlan, Erin ; Cahn, Wiepke ; de Zubicaray, Greig I ; Ehrlich, Stefan ; Ekström, Tomas J ; Flor, Herta ; Fröhner, Juliane H ; Frouin, Vincent ; Garavan, Hugh ; Gowland, Penny ; Heinz, Andreas ; Hoare, Jacqueline ; Ittermann, Bernd ; Jahanshad, Neda ; Jiang, Jiyang ; Kwok, John B ; Martin, Nicholas G ; Martinot, Jean-Luc ; Mather, Karen A ; McMahon, Katie L ; McRae, Allan F ; Nees, Frauke ; Papadopoulos Orfanos, Dimitri ; Paus, Tomáš ; Poustka, Luise ; Sämann, Philipp G ; Schofield, Peter R ; Smolka, Michael N ; Stein, Dan J ; Strike, Lachlan T ; Teeuw, Jalmar ; Thalamuthu, Anbupalam ; Trollor, Julian ; Walter, Henrik ; Wardlaw, Joanna M ; Wen, Wei ; Whelan, Robert ; Apostolova, Liana G ; Binder, Elisabeth B ; Boomsma, Dorret I ; Calhoun, Vince ; Crespo-Facorro, Benedicto ; Deary, Ian J ; Hulshoff Pol, Hilleke ; Ophoff, Roel A ; Pausova, Zdenka ; Sachdev, Perminder S ; Saykin, Andrew ; Wright, Margaret J ; Thompson, Paul M ; Schumann, Gunter ; van t Ent, Dennis ; Desrivières, Sylvane. / Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes : findings from the ENIGMA Epigenetics Working Group. In: Molecular Psychiatry. 2019.
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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 3337 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. 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 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 Evangelos Papastergios 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 {Roiz Santia{\~n}ez}, Roberto and Barbara Ruggeri and Daniil Sarkisyan and Jean Shin and Kim Sungeun and {Tordesillas Guti{\'e}rrez}, Diana 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 {Burke Quinlan}, Erin and Wiepke Cahn and {de Zubicaray}, {Greig I} and Stefan Ehrlich 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 Jacqueline Hoare and Bernd Ittermann and Neda Jahanshad and Jiyang Jiang and Kwok, {John B} and Martin, {Nicholas G} and Jean-Luc Martinot and Mather, {Karen A} and McMahon, {Katie L} and McRae, {Allan F} and Frauke Nees and {Papadopoulos Orfanos}, Dimitri and Tom{\'a}š Paus and Luise Poustka and S{\"a}mann, {Philipp G} and Schofield, {Peter R} and Smolka, {Michael N} and Stein, {Dan J} 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 {Hulshoff Pol}, Hilleke 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 {van t Ent}, Dennis and Sylvane Desrivi{\`e}res",
year = "2019",
month = "12",
day = "6",
doi = "10.1038/s41380-019-0605-z",
language = "English",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

}

Jia, T, Chu, C, Liu, Y, van Dongen, J, Papastergios, E, Armstrong, NJ, Bastin, ME, Carrillo-Roa, T, den Braber, A, Harris, M, Jansen, R, Liu, J, Luciano, M, Ori, APS, Roiz Santiañez, R, Ruggeri, B, Sarkisyan, D, Shin, J, Sungeun, K, Tordesillas Gutiérrez, D, Ames, D, Artiges, E, Bakalkin, G, Banaschewski, T, Bokde, ALW, Brodaty, H, Bromberg, U, Brouwer, R, Büchel, C, Burke Quinlan, E, Cahn, W, de Zubicaray, GI, Ehrlich, S, Ekström, TJ, Flor, H, Fröhner, JH, Frouin, V, Garavan, H, Gowland, P, Heinz, A, Hoare, J, Ittermann, B, Jahanshad, N, Jiang, J, Kwok, JB, Martin, NG, Martinot, J-L, Mather, KA, McMahon, KL, McRae, AF, Nees, F, Papadopoulos Orfanos, D, Paus, T, Poustka, L, Sämann, PG, Schofield, PR, Smolka, MN, Stein, DJ, 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, Hulshoff Pol, H, Ophoff, RA, Pausova, Z, Sachdev, PS, Saykin, A, Wright, MJ, Thompson, PM, Schumann, G, van t Ent, D & Desrivières, S 2019, 'Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group' Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0605-z

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes : findings from the ENIGMA Epigenetics Working Group. / Jia, Tianye; Chu, Congying; Liu, Yun; van Dongen, Jenny; Papastergios, Evangelos; Armstrong, Nicola J; Bastin, Mark E; Carrillo-Roa, Tania; den Braber, Anouk; Harris, Mathew; Jansen, Rick; Liu, Jingyu; Luciano, Michelle; Ori, Anil P S; Roiz Santiañez, Roberto; Ruggeri, Barbara; Sarkisyan, Daniil; Shin, Jean; Sungeun, Kim; Tordesillas Gutiérrez, Diana; Ames, David; Artiges, Eric; Bakalkin, Georgy; Banaschewski, Tobias; Bokde, Arun L W; Brodaty, Henry; Bromberg, Uli; Brouwer, Rachel; Büchel, Christian; Burke Quinlan, Erin; Cahn, Wiepke; de Zubicaray, Greig I; Ehrlich, Stefan; Ekström, Tomas J; Flor, Herta; Fröhner, Juliane H; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Heinz, Andreas; Hoare, Jacqueline; Ittermann, Bernd; Jahanshad, Neda; Jiang, Jiyang; Kwok, John B; Martin, Nicholas G; Martinot, Jean-Luc; Mather, Karen A; McMahon, Katie L; McRae, Allan F; Nees, Frauke; Papadopoulos Orfanos, Dimitri; Paus, Tomáš; Poustka, Luise; Sämann, Philipp G; Schofield, Peter R; Smolka, Michael N; Stein, Dan J; Strike, Lachlan T; Teeuw, Jalmar; Thalamuthu, Anbupalam; Trollor, Julian; Walter, Henrik; Wardlaw, Joanna M; Wen, Wei; Whelan, Robert; Apostolova, Liana G; Binder, Elisabeth B; Boomsma, Dorret I; Calhoun, Vince; Crespo-Facorro, Benedicto; Deary, Ian J; Hulshoff Pol, Hilleke; Ophoff, Roel A; Pausova, Zdenka; Sachdev, Perminder S; Saykin, Andrew; Wright, Margaret J; Thompson, Paul M; Schumann, Gunter; van t Ent, Dennis; Desrivières, Sylvane.

In: Molecular Psychiatry, 06.12.2019.

Research output: Contribution to JournalArticleAcademicpeer-review

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 - Papastergios, Evangelos

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 - Roiz Santiañez, Roberto

AU - Ruggeri, Barbara

AU - Sarkisyan, Daniil

AU - Shin, Jean

AU - Sungeun, Kim

AU - Tordesillas Gutiérrez, Diana

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 - Burke Quinlan, Erin

AU - Cahn, Wiepke

AU - de Zubicaray, Greig I

AU - Ehrlich, Stefan

AU - Ekström, Tomas J

AU - Flor, Herta

AU - Fröhner, Juliane H

AU - Frouin, Vincent

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Hoare, Jacqueline

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 - Papadopoulos Orfanos, Dimitri

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Sämann, Philipp G

AU - Schofield, Peter R

AU - Smolka, Michael N

AU - Stein, Dan J

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 - Hulshoff Pol, Hilleke

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 - van t Ent, Dennis

AU - Desrivières, Sylvane

PY - 2019/12/6

Y1 - 2019/12/6

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 3337 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. 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 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 3337 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. 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 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.

U2 - 10.1038/s41380-019-0605-z

DO - 10.1038/s41380-019-0605-z

M3 - Article

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -