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Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence

Abstract

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.

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Data availability

The 450K array data from brain tissues is available from the corresponding author upon request and signature of data transfer agreement. Aggregated summary statistics are available upon request.

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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.

IMAGEN Consortium

Tobias Banaschewski12, Gareth J. Barker13, Arun L. W. Bokde14, Erin Burke Quinlan15, Sylvane Desrivières15, Herta Flor16,17, Antoine Grigis18, Hugh Garavan19, Penny Gowland20, Andreas Heinz21, Bernd Ittermann22, Jean-Luc Martinot23,24, Marie-Laure Paillère Martinot25,26, Eric Artiges23,27, Frauke Nees12,16, Dimitri Papadopoulos Orfanos18, Herve Lemaitre18,28, Tomáš Paus29, Luise Poustka30, Sarah Hohmann12, Sabina Millenet12, Juliane H. Fröhner31, Michael N. Smolka31, Henrik Walter21, Robert Whelan32, Gunter Schumann15,33,34

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WM, LKS, OK, NT, DZ, DS, GB, TJE, JR, and YL conceived and conducted the experiments and analyses, with assistance from JRG, AI, WQ, HW, RA, HF, SB, DC, JMB, RDM, YD, VMK, and GS. YL, GB, JR, and TJE designed and coordinated the experiments. YL, TJE, and JR supervised the work. WM, TJE, JR, and YL wrote the manuscript with assistance from all authors.

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Correspondence to Tomas J. Ekström or Yun Liu.

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Meng, W., Sjöholm, L.K., Kononenko, O. et al. Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0588-9

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