TY - JOUR
T1 - Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence
AU - IMAGEN Consortium
AU - Meng, Weida
AU - Sjöholm, Louise K.
AU - Kononenko, Olga
AU - Tay, Nicole
AU - Zhang, Dandan
AU - Sarkisyan, Daniil
AU - Geske, Jennifer R.
AU - Ing, Alex
AU - Qiu, Wenqing
AU - Watanabe, Hiroyuki
AU - Almamoun, Radwa
AU - Frieling, Helge
AU - Bleich, Stefan
AU - Cui, Donghong
AU - Biernacka, Joanna M.
AU - Mayfield, R. Dayne
AU - Dang, Yongjun
AU - Karpyak, Victor M.
AU - Schumann, Gunter
AU - Banaschewski, Tobias
AU - Barker, Gareth J.
AU - Bokde, Arun L.W.
AU - Quinlan, Erin Burke
AU - Desrivières, Sylvane
AU - Flor, Herta
AU - Grigis, Antoine
AU - Garavan, Hugh
AU - Gowland, Penny
AU - Heinz, Andreas
AU - Ittermann, Bernd
AU - Martinot, Jean Luc
AU - Martinot, Marie Laure Paillère
AU - Artiges, Eric
AU - Nees, Frauke
AU - Orfanos, Dimitri Papadopoulos
AU - Lemaitre, Herve
AU - Paus, Tomáš
AU - Poustka, Luise
AU - Hohmann, Sarah
AU - Millenet, Sabina
AU - Fröhner, Juliane H.
AU - Smolka, Michael N.
AU - Walter, Henrik
AU - Whelan, Robert
AU - Bakalkin, Georgy
AU - Ekström, Tomas J.
AU - Rüegg, Joelle
AU - Liu, Yun
N1 - Funding Information:
Acknowledgements This work was supported by the grants from National Key R&D Program of China (No. 2017YFC0909200 to YL), the National Natural Science Foundation of China (No. 31771451 and No. 31471212 to YL) and Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01 and No. 2018SHZDZX01) and ZJLab; The Swedish Brain Foundation (FO2014-0223, F02016-0231, FO2018-0275 to TJE); the Swedish Research Council for Sustainable Development, Formas (No. 210-2012-1502 and 216-2013-1966 to JR); the Swedish Science Research Council (VR), and the Swedish Council for Working Life and Social Research (FORTE). We thank the New South Wales Brain Tissue Resource Centre (NSW BTRC) and the IMAGEN study group for contributing invaluable clinical information and biological samples. We thank Nashat Abumaria and Wei Li for the help on mouse behavioral testing. We thank Igor Bazov, Dongqing Jing and Nan-Jie Xu for the practical help, Philipp Antczak for proofreading the manuscript, and Richard Henriksson for the help with organizing the methylation analysis. IMAGEN Consortium received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907), the FP7 project MATRICS (603016), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: - ANR (project AF12-NEUR0008-01 - WM2NA, ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U. S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/8
Y1 - 2021/8
N2 - Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.
AB - Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.
UR - http://www.scopus.com/inward/record.url?scp=85075230843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075230843&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0588-9
DO - 10.1038/s41380-019-0588-9
M3 - Article
C2 - 31745236
AN - SCOPUS:85075230843
SN - 1359-4184
VL - 26
SP - 4367
EP - 4382
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -