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; Evangelous 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-Santianez; Barbara Ruggeri; Daniil Sarkisyan; Jean Shin; Kim Sungeun; Diana Tordesillas-Gutierrez; Dennis Van't Ent; David Ames; Eric Artiges; Georgy Bakalkin; Tobias Banaschewski; Arun L W Bokde; Henry Brodaty; Uli Bromberg; Rachel M Brouwer; Christian Büchel; Erin B. Quinlan; Wiepke Cahn; Greig I de Zubicaray; Stefan Ehrlich; Tomas J Ekström; Herta Flor; Juliane H Fröhner; Vincent Frouin; Hugh Garavan; Penny A Gowland; Andreas Heinz; Jacqueline Hoare; Bernd Ittermann; Neda Jahanshad; Jiyang Jiang; John B J Kwok; Nicholas G Martin; Jean-Luc Martinot; Karen A Mather; Katie L McMahon; Allan F. Mcrae; Frauke Nees; Dimitri Papadopoulos Orfanos; Tomas Paus; Luise Poustka; Philipp G Sämann; Peter R Schofield; Michael N Smolka; Dan J Stein; Lachlan T Strike; Jalmar Teeuw; Anbupalam Thalamuthu; Julian N. Trollor; Henrik Walter; Joanna M. Wardlaw; Wei Wen; Robert Whelan; Liana G Apostolova; Elisabeth B.  Binder; Dorrett Boomsma; Vince D Calhoun; Benedicto Crespo-Facorro; Ian J. Deary; Hilleke E. Hulshoff Pol; Roel A. Ophoff; Zdenka Pausova; Perminder S Sachdev; Andrew J Saykin; Margaret J Wright; Paul M. Thompson; Gunter Schumann; Sylvane Desrivières

doi: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

Tianye Jia, Congying Chu, Yun Liu, Jenny van Dongen, Evangelous 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-Santianez, Barbara Ruggeri, Daniil Sarkisyan, Jean Shin, Kim Sungeun, Diana Tordesillas-GutierrezDennis Van't Ent, David Ames, Eric Artiges, Georgy Bakalkin, Tobias Banaschewski, Arun L W Bokde, Henry Brodaty, Uli Bromberg, Rachel M Brouwer, Christian Büchel, Erin B. Quinlan, Wiepke Cahn, Greig I de Zubicaray, Stefan Ehrlich, Tomas J Ekström, Herta Flor, Juliane H Fröhner, Vincent Frouin, Hugh Garavan, Penny A Gowland, Andreas Heinz, Jacqueline Hoare, Bernd Ittermann, Neda Jahanshad, Jiyang Jiang, John B J Kwok, Nicholas G Martin, Jean-Luc Martinot, Karen A Mather, Katie L McMahon, Allan F. Mcrae, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomas Paus, Luise Poustka, Philipp G Sämann, Peter R Schofield, Michael N Smolka, Dan J Stein, Lachlan T Strike, Jalmar Teeuw, Anbupalam Thalamuthu, Julian N. Trollor, Henrik Walter, Joanna M. Wardlaw, Wei Wen, Robert Whelan, Liana G Apostolova, Elisabeth B. Binder, Dorrett Boomsma, Vince D Calhoun, Benedicto Crespo-Facorro, Ian J. Deary, Hilleke E. Hulshoff Pol, Roel A. Ophoff, Zdenka Pausova, Perminder S Sachdev, Andrew J Saykin, Margaret J Wright, Paul M. Thompson, Gunter Schumann, Sylvane Desrivières

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

Abstract / Description of output

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. 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 language	English
Pages (from-to)	1-12
Journal	Molecular Psychiatry
Volume	N/A
Early online date	6 Dec 2019
DOIs	https://doi.org/10.1038/s41380-019-0605-z
Publication status	E-pub ahead of print - 6 Dec 2019

Keywords / Materials (for Non-textual outputs)

genetics
molecular biology

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10.1038/s41380-019-0605-zLicence: Creative Commons: Attribution (CC-BY)

JiaEtalMP2019Epigenome-wideMeta-analysesOfBloodFinal published version, 1.68 MBLicence: Creative Commons: Attribution (CC-BY)

The Disconnected Mind Phase 3
Cox, S. & Deary, I.
1/04/16 → 31/03/23
Project: Research
Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III
Wardlaw, J., Bastin, M. & Deary, I.
MRC
1/05/15 → 30/04/19
Project: Research
RA2665 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Wardlaw, J.
1/09/13 → 31/08/19
Project: Research

Mark Bastin
- Deanery of Clinical Sciences - Personal Chair of Brain Imaging
- Centre for Clinical Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience
- Edinburgh Imaging
Person: Academic: Research Active

Cite this

Jia, T., Chu, C., Liu, Y., van Dongen, J., Papastergios, E., Armstrong, N. J., Bastin, M. E., Carrillo-roa, T., den Braber, A., Harris, M., Jansen, R., Liu, J., Luciano, M., Ori, A. P. S., Roiz-Santianez, R., Ruggeri, B., Sarkisyan, D., Shin, J., Sungeun, K., ... 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, N/A, 1-12. Advance online publication. https://doi.org/10.1038/s41380-019-0605-z

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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 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. 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.",

keywords = "genetics, molecular biology",

author = "Tianye Jia and Congying Chu and Yun Liu and {van Dongen}, Jenny and Evangelous 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 Roberto Roiz-Santianez and Barbara Ruggeri and Daniil Sarkisyan and Jean Shin and Kim Sungeun and Diana Tordesillas-Gutierrez 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 Brouwer, {Rachel M} and Christian B{\"u}chel and Quinlan, {Erin B.} 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 Gowland, {Penny A} and Andreas Heinz and Jacqueline Hoare and Bernd Ittermann and Neda Jahanshad and Jiyang Jiang and Kwok, {John B J} 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 Tomas 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 Trollor, {Julian N.} and Henrik Walter and Wardlaw, {Joanna M.} and Wei Wen and Robert Whelan and Apostolova, {Liana G} and Binder, {Elisabeth B.} and Dorrett Boomsma and Calhoun, {Vince D} and Benedicto Crespo-Facorro and Deary, {Ian J.} and {Hulshoff Pol}, {Hilleke E.} and Ophoff, {Roel A.} and Zdenka Pausova and Sachdev, {Perminder S} and Saykin, {Andrew J} and Wright, {Margaret J} and Thompson, {Paul M.} and Gunter Schumann and Sylvane Desrivi{\`e}res",

year = "2019",

month = dec,

day = "6",

doi = "10.1038/s41380-019-0605-z",

language = "English",

volume = "N/A",

pages = "1--12",

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-Santianez, R, Ruggeri, B, Sarkisyan, D, Shin, J, Sungeun, K, Tordesillas-Gutierrez, D, Van't Ent, D, Ames, D, Artiges, E, Bakalkin, G, Banaschewski, T, Bokde, ALW, Brodaty, H, Bromberg, U, Brouwer, RM, Büchel, C, Quinlan, EB, Cahn, W, de Zubicaray, GI, Ehrlich, S, Ekström, TJ, Flor, H, Fröhner, JH, Frouin, V, Garavan, H, Gowland, PA, Heinz, A, Hoare, J, Ittermann, B, Jahanshad, N, Jiang, J, Kwok, JBJ, 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, JN, Walter, H, Wardlaw, JM, Wen, W, Whelan, R, Apostolova, LG, Binder, EB, Boomsma, D, Calhoun, VD, Crespo-Facorro, B, Deary, IJ, Hulshoff Pol, HE, Ophoff, RA, Pausova, Z, Sachdev, PS, Saykin, AJ, Wright, MJ, Thompson, PM, Schumann, G & 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, vol. N/A, pp. 1-12. https://doi.org/10.1038/s41380-019-0605-z

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, Evangelous

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-Santianez, Roberto

AU - Ruggeri, Barbara

AU - Sarkisyan, Daniil

AU - Shin, Jean

AU - Sungeun, Kim

AU - Tordesillas-Gutierrez, Diana

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 M

AU - Büchel, Christian

AU - Quinlan, Erin B.

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 A

AU - Heinz, Andreas

AU - Hoare, Jacqueline

AU - Ittermann, Bernd

AU - Jahanshad, Neda

AU - Jiang, Jiyang

AU - Kwok, John B J

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, Tomas

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 N.

AU - Walter, Henrik

AU - Wardlaw, Joanna M.

AU - Wen, Wei

AU - Whelan, Robert

AU - Apostolova, Liana G

AU - Binder, Elisabeth B.

AU - Boomsma, Dorrett

AU - Calhoun, Vince D

AU - Crespo-Facorro, Benedicto

AU - Deary, Ian J.

AU - Hulshoff Pol, Hilleke E.

AU - Ophoff, Roel A.

AU - Pausova, Zdenka

AU - Sachdev, Perminder S

AU - Saykin, Andrew J

AU - Wright, Margaret J

AU - Thompson, Paul M.

AU - Schumann, Gunter

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 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. 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 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. 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.

KW - genetics

KW - molecular biology

U2 - 10.1038/s41380-019-0605-z

DO - 10.1038/s41380-019-0605-z

M3 - Article

SN - 1359-4184

VL - N/A

SP - 1

EP - 12

JO - Molecular Psychiatry

JF - Molecular Psychiatry

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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Keywords / Materials (for Non-textual outputs)

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Projects

The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

RA2665 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

Profiles

Mark Bastin

Cite this