Journal Article

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

Stein, Dan J, Whelan, Robert, Frouin Vincent, Hoare, Jacqueline, Wen, Wei, Ehrlich, Stefan, Martinot Jean-Luc, Carrillo-Roa, Tania, Armstrong, Nicola J, Ekström, Tomas J, Thalamuthu Anbupalam, McRae, Allan F, Bromberg Uli, Ruggeri, Barbara, Harris, Mathew, Teeuw Jalmar, Pausova Zdenka, Papadopoulos, Orfanos Dimitri, Smolka, Michael N, Brodaty Henry, Schofield, Peter R, Gowland, Penny, Cahn Wiepke, Ittermann Bernd, Poustka Luise, Thompson, Paul M, Jansen, Rick, Liu, Yun, van’t Ent Dennis, Ames, David, Apostolova, Liana G, Kwok, John B, Banaschewski Tobias, Walter, Henrik, Ophoff, Roel A, Hulshoff Pol Hilleke, Papastergios Evangelos, Jia Tianye, Trollor Julian, Sylvane, Desrivières, Artiges Eric, Mather, Karen A, Paus Tomáš, Büchel, Christian, den Braber Anouk, Sachdev, Perminder S, Nees Frauke, Jiang Jiyang, Heinz, Andreas, Luciano, Michelle, Sarkisyan Daniil, Flor Herta, van Dongen Jenny, Brouwer, Rachel, Wright, Margaret J, Greig, de Zubicaray, Bakalkin Georgy, Calhoun, Vince, Bastin, Mark E, Roiz Santiañez Roberto, Martin, Nicholas G, Deary, Ian J, Saykin, Andrew, Ori, Anil P, Garavan Hugh, Boomsma Dorret I, Tord

2021

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Biomarkers / Blood / Cell differentiation / Deoxyribonucleic acid / Diabetes mellitus / DNA / DNA fingerprinting / DNA methylation / Epigenetics / Gene expression / Genetic diversity / Genetic factors / Genomes / Heritability / Hippocampus / Meta-analysis / Neurodegeneration / Nucleus accumbens / Phenotypes / Stem cells / Systematic review / Thalamus