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

Molecular Psychiatry volume 26, pages 4367–4382 (2021)Cite this article

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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.

References

  1. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet. 2009;373:2223–33.

    PubMed  Google Scholar 

  2. Starkman BG, Sakharkar AJ, Pandey SC. Epigenetics-beyond the genome in alcoholism. Alcohol Res. 2012;34:293–305.

    PubMed  PubMed Central  Google Scholar 

  3. Heath AC, Bucholz KK, Madden PA, Dinwiddie SH, Slutske WS, Bierut LJ, et al. Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol Med. 1997;27:1381–96.

    CAS  PubMed  Google Scholar 

  4. Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ. A population-based twin study of alcoholism in women. JAMA. 1992;268:1877–82.

    CAS  PubMed  Google Scholar 

  5. McGue M, Pickens RW, Svikis DS. Sex and age effects on the inheritance of alcohol problems: a twin study. J Abnorm Psychol. 1992;101:3–17.

    CAS  PubMed  Google Scholar 

  6. Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry. 1999;156:34–40.

    CAS  PubMed  Google Scholar 

  7. Reed T, Page WF, Viken RJ, Christian JC. Genetic predisposition to organ-specific endpoints of alcoholism. Alcohol Clin Exp Res. 1996;20:1528–33.

    CAS  PubMed  Google Scholar 

  8. Verhulst B, Neale MC, Kendler KS. The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med. 2015;45:1061–72.

    CAS  PubMed  Google Scholar 

  9. Park BL, Kim JW, Cheong HS, Kim LH, Lee BC, Seo CH, et al. Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication. Hum Genet. 2013;132:657–68.

    CAS  PubMed  Google Scholar 

  10. Gelernter J, Kranzler HR, Sherva R, Koesterer R, Almasy L, Zhao H, et al. Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways. Biol Psychiatry. 2014;76:66–74.

    CAS  PubMed  Google Scholar 

  11. Walters RK, Polimanti R, Johnson EC, McClintick JN, Adams MJ, Adkins AE, et al. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. Nat Neurosci. 2018;21:1656–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Mardones J, Segovia-Riquelme N. Thirty-two years of selection of rats by ethanol preference: UChA and UChB strains. Neurobehav Toxicol Teratol. 1983;5:171–8.

    CAS  PubMed  Google Scholar 

  13. Crabbe JC, Metten P, Rhodes JS, Yu C-H, Brown LL, Phillips TJ, et al. A line of mice selected for high blood ethanol concentrations shows drinking in the dark to intoxication. Biol Psychiatry. 2009;65:662–70.

    CAS  PubMed  Google Scholar 

  14. Schumann G, Liu C, O’Reilly P, Gao H, Song P, Xu B, et al. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci USA. 2016;113:14372–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zakhari S. Alcohol metabolism and epigenetics changes. Alcohol Res. 2013;35:6–16.

    PubMed  PubMed Central  Google Scholar 

  16. Zhang H, Herman AI, Kranzler HR, Anton RF, Simen AA, Gelernter J. Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence. J Hum Genet. 2012;57:670–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489:75–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Philibert RA, Gunter TD, Beach SRH, Brody GH, Madan A. MAOA methylation is associated with nicotine and alcohol dependence in women. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:565–70.

    CAS  PubMed  Google Scholar 

  19. Taqi MM, Bazov I, Watanabe H, Sheedy D, Harper C, Alkass K, et al. Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics. Addict Biol. 2011;16:499–509.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Manzardo AM, Henkhaus RS, Butler MG. Global DNA promoter methylation in frontal cortex of alcoholics and controls. Gene. 2012;498:5–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang F, Xu H, Zhao H, Gelernter J, Zhang H. DNA co-methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders. Sci Rep. 2016;6:19430.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Harper C, Kril J, Daly J. Does a ‘moderate’ alcohol intake damage the brain? J Neurol Neurosurg Psychiatry. 1988;51:909–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Schumann G, Loth E, Banaschewski T, Barbot A, Barker G, Büchel C, et al. The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology. Mol Psychiatry. 2010;15:1128–39.

    CAS  PubMed  Google Scholar 

  24. Whelan R, Watts R, Orr CA, Althoff RR, Artiges E, Banaschewski T, et al. Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature. 2014;512:185–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, et al. Minfi: a flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30:1363–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8:290–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kononenko O, Bazov I, Watanabe H, Gerashchenko G, Dyachok O, Verbeek DS, et al. Opioid precursor protein isoform is targeted to the cell nuclei in the human brain. Biochim Biophys Acta, Gen Subj. 2017;1861:246–55.

    CAS  Google Scholar 

  28. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisén J. Retrospective birth dating of cells in humans. Cell. 2005;122:133–43.

    CAS  PubMed  Google Scholar 

  29. Dammer EB, Duong DM, Diner I, Gearing M, Feng Y, Lah JJ, et al. Neuron enriched nuclear proteome isolated from human brain. J Proteome Res. 2013;12:3193–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hannon E, Lunnon K, Schalkwyk L, Mill J. Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes. Epigenetics. 2015;10:1024–32.

    PubMed  PubMed Central  Google Scholar 

  31. Qiu W, Xu Z, Zhang M, Zhang D, Fan H, Li T, et al. Determination of local chromatin interactions using a combined CRISPR and peroxidase APEX2 system. Nucleic Acids Res. 2019;47:e52.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu Z, Meng W, Liu P, Zhu X, Liu Y, Zou H. DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding. Clin Epigenetics. 2017;9:99.

    PubMed  PubMed Central  Google Scholar 

  33. Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, et al. NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci. 2015;18:545–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lowery-Gionta EG, Navarro M, Li C, Pleil KE, Rinker JA, Cox BR, et al. Corticotropin releasing factor signaling in the central amygdala is recruited during binge-like ethanol consumption in C57BL/6J mice. J Neurosci. 2012;32:3405–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hannon E, Knox O, Sugden K, Burrage J, Wong CCY, Belsky DW, et al. Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins. PLoS Genet. 2018;14:e1007544.

    PubMed  PubMed Central  Google Scholar 

  36. Takeuchi M, Hata Y, Hirao K, Toyoda A, Irie M, Takai Y. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J Biol Chem. 1997;272:11943–51.

    CAS  PubMed  Google Scholar 

  37. Liu Y, Li X, Aryee MJ, Ekström TJ, Padyukov L, Klareskog L, et al. GeMes, clusters of DNA methylation under genetic control, can inform genetic and epigenetic analysis of disease. Am J Hum Genet. 2014;94:485–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31:142–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le JM, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011;98:288–95.

    CAS  PubMed  Google Scholar 

  40. Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MPM, van Eijk K, et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012;13:R97.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Knutson B, Adams CM, Fong GW, Hommer D. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci. 2001;21:RC159.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Aloi J, Blair KS, Crum KI, Meffert H, White SF, Tyler PM, et al. Adolescents show differential dysfunctions related to Alcohol and Cannabis Use Disorder severity in emotion and executive attention neuro-circuitries. NeuroImage Clin. 2018;19:782–92.

    PubMed  PubMed Central  Google Scholar 

  43. Zilverstand A, Huang AS, Alia-Klein N, Goldstein RZ. Neuroimaging impaired response inhibition and salience attribution in human drug addiction: a systematic review. Neuron. 2018;98:886–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Seo D, Lacadie CM, Tuit K, Hong K-I, Constable RT, Sinha R. Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk. JAMA Psychiatry. 2013;70:727–39.

    PubMed  PubMed Central  Google Scholar 

  45. Zhao J, Tomasi D, Wiers CE, Shokri-Kojori E, Demiral ŞB, Zhang Y, et al. Correlation between traits of emotion-based impulsivity and intrinsic default-mode network activity. Neural Plast. 2017;2017:9297621.

    PubMed  PubMed Central  Google Scholar 

  46. Natarajan A, Yardimci GG, Sheffield NC, Crawford GE, Ohler U. Predicting cell-type-specific gene expression from regions of open chromatin. Genome Res. 2012;22:1711–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

    Google Scholar 

  48. Neph S, Vierstra J, Stergachis AB, Reynolds AP, Haugen E, Vernot B, et al. An expansive human regulatory lexicon encoded in transcription factor footprints. Nature. 2012;489:83–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhang Y, An L, Xu J, Zhang B, Zheng WJ, Hu M, et al. Enhancing Hi-C data resolution with deep convolutional neural network HiCPlus. Nat Commun. 2018;9:750.

    PubMed  PubMed Central  Google Scholar 

  50. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteom. 2014;13:397–406.

    CAS  Google Scholar 

  51. Li J, Zhang W, Yang H, Howrigan DP, Wilkinson B, Souaiaia T, et al. Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders. Nat Neurosci. 2017;20:1150–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shi S, Lin S, Chen B, Zhou Y. Isolated chromosome 8p23.2-pter deletion: Novel evidence for developmental delay, intellectual disability, microcephaly and neurobehavioral disorders. Mol Med Rep. 2017;16:6837–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chien W-H, Gau SS-F, Liao H-M, Chiu Y-N, Wu Y-Y, Huang Y-S, et al. Deep exon resequencing of DLGAP2 as a candidate gene of autism spectrum disorders. Mol Autism. 2013;4:26.

    PubMed  PubMed Central  Google Scholar 

  54. Jiang-Xie L-F, Liao H-M, Chen C-H, Chen Y-T, Ho S-Y, Lu D-H, et al. Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits. Mol Autism. 2014;5:32.

    PubMed  PubMed Central  Google Scholar 

  55. Rasmussen AH, Rasmussen HB, Silahtaroglu A. The DLGAP family: neuronal expression, function and role in brain disorders. Mol Brain. 2017;10:43.

    PubMed  PubMed Central  Google Scholar 

  56. Xing J, Kimura H, Wang C, Ishizuka K, Kushima I, Arioka Y, et al. Resequencing and association analysis of six PSD-95-related genes as possible susceptibility genes for schizophrenia and autism spectrum disorders. Sci Rep. 2016;6:27491.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Li J-M, Lu C-L, Cheng M-C, Luu S-U, Hsu S-H, Hu T-M, et al. Role of the DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 in schizophrenia. PLoS ONE. 2014;9:e85373.

    PubMed  PubMed Central  Google Scholar 

  58. Chaudhry M, Wang X, Bamne MN, Hasnain S, Demirci FY, Lopez OL, et al. Genetic variation in imprinted genes is associated with risk of late-onset Alzheimer’s disease. J Alzheimers Dis. 2015;44:989–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kular L, Liu Y, Ruhrmann S, Zheleznyakova G, Marabita F, Gomez-Cabrero D, et al. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat Commun. 2018;9:2397.

    PubMed  PubMed Central  Google Scholar 

  60. Meng W, Zhu Z, Jiang X, Too CL, Uebe S, Jagodic M, et al. DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis. Arthritis Res Ther. 2017;19:71.

    PubMed  PubMed Central  Google Scholar 

  61. Camp MC, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson R-M, et al. A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol. 2011;16:428–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Luedi PP, Dietrich FS, Weidman JR, Bosko JM, Jirtle RL, Hartemink AJ. Computational and experimental identification of novel human imprinted genes. Genome Res. 2007;17:1723–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Strogantsev R, Krueger F, Yamazawa K, Shi H, Gould P, Goldman-Roberts M, et al. Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression. Genome Biol. 2015;16:112.

    PubMed  PubMed Central  Google Scholar 

  64. Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10:561–72.

    CAS  PubMed  Google Scholar 

  65. Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374:363–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gilpin NW, Koob GF. Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res Health. 2008;31:185–95.

    PubMed  PubMed Central  Google Scholar 

  67. Zeng M, Chen X, Guan D, Xu J, Wu H, Tong P, et al. Reconstituted postsynaptic density as a molecular platform for understanding synapse formation and plasticity. Cell. 2018;174:1172–.e16.

    CAS  PubMed  Google Scholar 

  68. Bats C, Groc L, Choquet D. The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron. 2007;53:719–34.

    CAS  PubMed  Google Scholar 

  69. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995;269:1737–40.

    CAS  PubMed  Google Scholar 

  70. Coba MP, Ramaker MJ, Ho EV, Thompson SL, Komiyama NH, Grant SGN, et al. Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability. Sci Rep. 2018;8:2281.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding J-D, et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature. 2007;448:894–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Schob C, Morellini F, Ohana O, Bakota L, Hrynchak MV, Brandt R, et al. Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice. Transl Psychiatry. 2019;9:7.

    PubMed  PubMed Central  Google Scholar 

  73. Dawson DA, Grant BF, Li T-K. Quantifying the risks associated with exceeding recommended drinking limits. Alcohol Clin Exp Res. 2005;29:902–8.

    PubMed  Google Scholar 

  74. Grant JD, Scherrer JF, Lynskey MT, Lyons MJ, Eisen SA, Tsuang MT, et al. Adolescent alcohol use is a risk factor for adult alcohol and drug dependence: evidence from a twin design. Psychol Med. 2006;36:109–18.

    PubMed  Google Scholar 

Download references

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

Author information

Author notes

  1. These authors contributed equally: Weida Meng, Louise K. Sjöholm, Olga Kononenko, Nicole Tay, Dandan Zhang, Daniil Sarkisyan, Georgy Bakalkin, Tomas J. Ekström, Joelle Rüegg, Yun Liu

Authors and Affiliations

  1. MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China

    Weida Meng, Dandan Zhang, Wenqing Qiu, Yongjun Dang & Yun Liu

  2. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China

    Weida Meng, Dandan Zhang, Wenqing Qiu & Yun Liu

  3. Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    Louise K. Sjöholm, Radwa Almamoun & Tomas J. Ekström

  4. Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Olga Kononenko, Daniil Sarkisyan, Hiroyuki Watanabe & Georgy Bakalkin

  5. Centre for Population Neuroscience and Stratified Medicine (PONS), Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Nicole Tay, Alex Ing & Gunter Schumann

  6. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Jennifer R. Geske

  7. Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany

    Helge Frieling & Stefan Bleich

  8. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Donghong Cui

  9. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    Joanna M. Biernacka & Victor M. Karpyak

  10. The Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA

    R. Dayne Mayfield

  11. Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Joelle Rüegg

  12. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159, Mannheim, Germany

    Tobias Banaschewski, Frauke Nees, Sarah Hohmann & Sabina Millenet

  13. Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Gareth J. Barker

  14. Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

    Arun L. W. Bokde

  15. Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology & Neuroscience, SGDP Centre, King’s College London, London, UK

    Erin Burke Quinlan, Sylvane Desrivières & Gunter Schumann

  16. Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany

    Herta Flor & Frauke Nees

  17. Department of Psychology, School of Social Sciences, University of Mannheim, 68131, Mannheim, Germany

    Herta Flor

  18. NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France

    Antoine Grigis, Dimitri Papadopoulos Orfanos & Herve Lemaitre

  19. Departments of Psychiatry and Psychology, University of Vermont, 05405, Burlington, VT, USA

    Hugh Garavan

  20. Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK

    Penny Gowland

  21. Department of Psychiatry and Psychotherapy CCM, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Andreas Heinz & Henrik Walter

  22. Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Germany

    Bernd Ittermann

  23. Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 “Neuroimaging & Psychiatry”, University Paris Saclay, University Paris Descartes—Sorbonne Paris Cité, Paris, France

    Jean-Luc Martinot & Eric Artiges

  24. Maison de Solenn, Paris, France

    Jean-Luc Martinot

  25. Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 “Neuroimaging & Psychiatry”, University Paris Sacaly, University Paris Descartes, Paris, France

    Marie-Laure Paillère Martinot

  26. AP-HP Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France

    Marie-Laure Paillère Martinot

  27. Psychiatry Department 91G16, Orsay Hospital, Orsay, France

    Eric Artiges

  28. Institut National de la Santé et de la Recherche Médicale, UMR 992 INSERM, CEA, Faculté de médecine, Université Paris-Sud, Université Paris-Saclay, NeuroSpin, F-91191, Gif-sur-Yvette, France

    Herve Lemaitre

  29. Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, M6A 2E1, Canada

    Tomáš Paus

  30. Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany

    Luise Poustka

  31. Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany

    Juliane H. Fröhner & Michael N. Smolka

  32. School of Psychology and Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland

    Robert Whelan

  33. PONS Research Group, Department of Psychiatry and Psychotherapy, Campus Charite Mitte, Humboldt University, Berlin and Leibniz Institute for Neurobiology, Magdeburg, Germany

    Gunter Schumann

  34. Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China

    Gunter Schumann

Authors
  1. Weida Meng
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  2. Louise K. Sjöholm
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  3. Olga Kononenko
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  4. Nicole Tay
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  5. Dandan Zhang
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  6. Daniil Sarkisyan
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  7. Jennifer R. Geske
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  8. Alex Ing
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  9. Wenqing Qiu
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  10. Hiroyuki Watanabe
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  11. Radwa Almamoun
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  12. Helge Frieling
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  13. Stefan Bleich
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  14. Donghong Cui
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  15. Joanna M. Biernacka
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  16. R. Dayne Mayfield
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  17. Yongjun Dang
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  18. Victor M. Karpyak
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  19. Gunter Schumann
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  20. Georgy Bakalkin
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  21. Tomas J. Ekström
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  22. Joelle Rüegg
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  23. Yun Liu
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Consortia

IMAGEN Consortium

  • Tobias Banaschewski
  • , Gareth J. Barker
  • , Arun L. W. Bokde
  • , Erin Burke Quinlan
  • , Sylvane Desrivières
  • , Herta Flor
  • , Antoine Grigis
  • , Hugh Garavan
  • , Penny Gowland
  • , Andreas Heinz
  • , Bernd Ittermann
  • , Jean-Luc Martinot
  • , Marie-Laure Paillère Martinot
  • , Eric Artiges
  • , Frauke Nees
  • , Dimitri Papadopoulos Orfanos
  • , Herve Lemaitre
  • , Tomáš Paus
  • , Luise Poustka
  • , Sarah Hohmann
  • , Sabina Millenet
  • , Juliane H. Fröhner
  • , Michael N. Smolka
  • , Henrik Walter
  • , Robert Whelan
  •  & Gunter Schumann

Contributions

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.

Corresponding authors

Correspondence to Tomas J. Ekström or Yun Liu.

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Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Members of the IMAGEN Consortium are listed after Acknowledgements.

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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 26, 4367–4382 (2021). https://doi.org/10.1038/s41380-019-0588-9

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  • DOI: https://doi.org/10.1038/s41380-019-0588-9

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