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

By Tianye Jia, Congying Chu, Yun Liu, Jenny van Dongen, 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 Brouwer, Christian Buchel, Erin Burke Quinlan, Wiepke Cahn, Greig I. de Zubicaray, Tomas J. Ekstrom, Herta Flor, Juliane H. Frohner, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Neda Jahanshad, Jiyang Jiang, John 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. Samann, Peter Schofield, Michael N. Smolka, Lachlan T. Strike, Jalmar Teeuw, Anbupalam Thalamuthu, Julian Trollor, Henrik Walter, Joanna M Wardlaw, Wei Wen, Robert Whelan, Liana G. Apostolova, Elisabeth B. Binder, Dorret I Boomsma, Vince Calhoun, Benedicto Crespo-Facorro, Ian J Deary, Hilleke Hulshoff Pol, Roel A. Ophoff, Zdenka Pausova, Perminder S. Sachdev, Andrew Saykin, Margaret J Wright, Paul M Thompson, Gunter Schumann, Sylvane Desrivieres

Posted 05 Nov 2018
bioRxiv DOI: 10.1101/460444

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.

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