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

TY - JOUR

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

AU - IMAGEN Consortium

PY - 2021/8

Y1 - 2021/8

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 - SCORING: Journal article

C2 - 31811260

VL - 26

SP - 3884

EP - 3895

JO - MOL PSYCHIATR

JF - MOL PSYCHIATR

SN - 1359-4184

IS - 8

ER -