Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
ABSTRACT 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.
Trollor Julian、Calhoun Vince、Bokde Arun L.W.、B¨1chel Christian、de Zubicaray Greig I.、Ekstr?m Tomas J.、Flor Herta、Frouin Vincent、Garavan Hugh、Heinz Andreas、Nees Frauke、Paus Tom¨￠?、Poustka Luise、Smolka Michael N.、Strike Lachlan T.、Thalamuthu Anbupalam、Walter Henrik、Wardlaw Joanna M.、Wen Wei、Apostolova Liana G.、Pausova Zdenka、Sachdev Perminder S.、Thompson Paul M.、Jia Tianye、Dongen Jenny van、Bastin Mark E.、Carrillo-Roa Tania、Jansen Rick、Ori Anil P.S.、Santia?ez Roberto Roiz、Sarkisyan Daniil、Shin Jean、Ames David、Bakalkin Georgy、Banaschewski Tobias、Harris Mathew、Brodaty Henry、Crespo-Facorro Benedicto、Desrivi¨¨res Sylvane、Guti¨|rrez Diana Tordesillas、Martin Nicholas G.、Jahanshad Neda、Deary Ian J.、Ruggeri Barbara、Luciano Michelle、Brouwer Rachel、Martinot Jean-Luc、Liu Jingyu、Bromberg Uli、Whelan Robert、McMahon Katie L.、Gowland Penny、Armstrong Nicola J、Teeuw Jalmar、Schumann Gunter、Saykin Andrew、Fr?hner Juliane H.、Ittermann Bernd、Sungeun Kim、Wright Margaret J.、Binder Elisabeth B.、S?mann Philipp G.、Ophoff Roel A.、Orfanos Dimitri Papadopoulos、Ent Dennis van?ˉt、Cahn Wiepke、Pol Hilleke Hulshoff、McRae Allan F.、Kwok John B.、Braber Anouk den、Chu Congying、Artiges Eric、Boomsma Dorret I.、Jiang Jiyang、Liu Yun、Schofield Peter R.、Quinlan Erin Burke、Mather Karen A.
基础医学神经病学、精神病学分子生物学
Trollor Julian,Calhoun Vince,Bokde Arun L.W.,B¨1chel Christian,de Zubicaray Greig I.,Ekstr?m Tomas J.,Flor Herta,Frouin Vincent,Garavan Hugh,Heinz Andreas,Nees Frauke,Paus Tom¨￠?,Poustka Luise,Smolka Michael N.,Strike Lachlan T.,Thalamuthu Anbupalam,Walter Henrik,Wardlaw Joanna M.,Wen Wei,Apostolova Liana G.,Pausova Zdenka,Sachdev Perminder S.,Thompson Paul M.,Jia Tianye,Dongen Jenny van,Bastin Mark E.,Carrillo-Roa Tania,Jansen Rick,Ori Anil P.S.,Santia?ez Roberto Roiz,Sarkisyan Daniil,Shin Jean,Ames David,Bakalkin Georgy,Banaschewski Tobias,Harris Mathew,Brodaty Henry,Crespo-Facorro Benedicto,Desrivi¨¨res Sylvane,Guti¨|rrez Diana Tordesillas,Martin Nicholas G.,Jahanshad Neda,Deary Ian J.,Ruggeri Barbara,Luciano Michelle,Brouwer Rachel,Martinot Jean-Luc,Liu Jingyu,Bromberg Uli,Whelan Robert,McMahon Katie L.,Gowland Penny,Armstrong Nicola J,Teeuw Jalmar,Schumann Gunter,Saykin Andrew,Fr?hner Juliane H.,Ittermann Bernd,Sungeun Kim,Wright Margaret J.,Binder Elisabeth B.,S?mann Philipp G.,Ophoff Roel A.,Orfanos Dimitri Papadopoulos,Ent Dennis van?ˉt,Cahn Wiepke,Pol Hilleke Hulshoff,McRae Allan F.,Kwok John B.,Braber Anouk den,Chu Congying,Artiges Eric,Boomsma Dorret I.,Jiang Jiyang,Liu Yun,Schofield Peter R.,Quinlan Erin Burke,Mather Karen A..Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group[EB/OL].(2025-03-28)[2025-08-14].https://www.biorxiv.org/content/10.1101/460444.点此复制
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