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
AU - ENIGMA Epigenetics Working Group
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.
UR - http://www.scopus.com/inward/record.url?scp=85076442903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076442903&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0605-z
DO - 10.1038/s41380-019-0605-z
M3 - Article
C2 - 31811260
SN - 1359-4184
VL - 26
SP - 3884
EP - 3895
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -