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

Weida Meng; Louise K Sjöholm; Olga Kononenko; Nicole Tay; Dandan Zhang; Daniil Sarkisyan; Jennifer R Geske; Alex Ing; Wenqing Qiu; Hiroyuki Watanabe; Radwa Almamoun; Helge Frieling; Stefan Bleich; Donghong Cui; Joanna M Biernacka; R Dayne Mayfield; Yongjun Dang; Victor M Karpyak; Gunter Schumann; IMAGEN Consortium; Georgy Bakalkin; Tomas J Ekström; Joelle Rüegg; Yun Liu

doi:10.1038/s41380-019-0588-9

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

Mol Psychiatry. 2021 Aug;26(8):4367-4382. doi: 10.1038/s41380-019-0588-9. Epub 2019 Nov 19.

Authors

Weida Meng^#^{1

2}, Louise K Sjöholm^#³, Olga Kononenko^#⁴, Nicole Tay^#⁵, Dandan Zhang^#^{1

2}, Daniil Sarkisyan^#⁴, Jennifer R Geske⁶, Alex Ing⁵, Wenqing Qiu^{1

2}, Hiroyuki Watanabe⁴, Radwa Almamoun³, Helge Frieling⁷, Stefan Bleich⁷, Donghong Cui⁸, Joanna M Biernacka⁹, R Dayne Mayfield¹⁰, Yongjun Dang¹, Victor M Karpyak⁹, Gunter Schumann⁵; IMAGEN Consortium; Georgy Bakalkin^#⁴, Tomas J Ekström^#¹¹, Joelle Rüegg^#¹², Yun Liu^#^{13

14}

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.
² State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
³ Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴ Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
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.
⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁷ Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany.
⁸ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁹ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
¹⁰ The Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
¹¹ Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. tomas.ekstrom@ki.se.
¹² Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³ 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. yliu39@fudan.edu.cn.
¹⁴ State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China. yliu39@fudan.edu.cn.

^# Contributed equally.

PMID: 31745236
DOI: 10.1038/s41380-019-0588-9

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Drinking* / genetics
Alcoholism / genetics*
Animals
DNA Methylation*
Epigenesis, Genetic*
Epigenome
Genotype
Mice
Nerve Tissue Proteins / genetics*

Substances

Dlgap2 protein, mouse
Nerve Tissue Proteins

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

Authors

Collaborators

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding