Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
Authors: Jia Tianye , Chu Congying , Liu Yun , Dongen Jenny van , Armstrong Nicola J , Bastin Mark E. , Carrillo-Roa Tania , Braber Anouk den , Harris Mathew , Jansen Rick , Liu Jingyu , Luciano Michelle , Ori Anil P.S. , Santiañez Roberto Roiz , Ruggeri Barbara , Sarkisyan Daniil , Shin Jean , Sungeun Kim , Gutiérrez Diana Tordesillas , Ent Dennis van’t , Ames David , Artiges Eric , Bakalkin Georgy , Banaschewski Tobias , Bokde Arun L.W. , Brodaty Henry , Bromberg Uli , Brouwer Rachel , Büchel Christian , Quinlan Erin Burke , Cahn Wiepke , de Zubicaray Greig I. , Ekström Tomas J. , Flor Herta , Fröhner Juliane H. , Frouin Vincent , Garavan Hugh , Gowland Penny , Heinz Andreas , 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 , Orfanos Dimitri Papadopoulos , Paus Tomáš , Poustka Luise , Sämann Philipp G. , Schofield Peter R. , Smolka Michael N. , 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. , Pol Hilleke Hulshoff , Ophoff Roel A. , Pausova Zdenka , Sachdev Perminder S. , Saykin Andrew , Wright Margaret J. , Thompson Paul M. , Schumann Gunter , Desrivières Sylvane 
Published: November 2018

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. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. 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 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.