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

• Published in: Molecular psychiatry Vol. 26; no. 8; pp. 4367 - 4382
• Main Authors: Meng, Weida, Sjöholm, Louise K., Kononenko, Olga, Tay, Nicole, Zhang, Dandan, Sarkisyan, Daniil, Geske, Jennifer R., Ing, Alex, Qiu, Wenqing, Watanabe, Hiroyuki, Almamoun, Radwa, Frieling, Helge, Bleich, Stefan, Cui, Donghong, Biernacka, Joanna M., Mayfield, R. Dayne, Dang, Yongjun, Karpyak, Victor M., Schumann, Gunter, Bakalkin, Georgy, Ekström, Tomas J., Rüegg, Joelle, Liu, Yun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2021; Nature Publishing Group
• Subjects: 45/43; 45/61; 59/57; 631/208; 631/337; 64/60; 692/699/476/5; Alcohol Drinking - genetics; Alcohol use; Alcoholism; Alcoholism - genetics; Animals; Association analysis; Behavioral Sciences; Biological Psychology; Brain; DNA Methylation; Drug dependence; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Epigenome; Gene expression; Genetic aspects; Genotype; Genotypes; Health aspects; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Methylation; Mice; Nerve Tissue Proteins - genetics; Neurosciences; Pharmacotherapy; Physiological aspects; Psychiatry; Public health; Reinforcement; Risk factors; Australia
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-019-0588-9

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.