{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:58:22Z","timestamp":1787828302771,"version":"build-2784847793"},"reference-count":67,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271560"],"award-info":[{"award-number":["82271560"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and aims<\/jats:title><jats:p>Whether alcohol\u2010related DNA methylation has a causal effect on psychiatric disorders has not been investigated. Furthermore, a comprehensive investigation into the causal relationship and underlying mechanisms linking alcohol consumption and psychiatric disorders has been lacking. This study aimed to evaluate the causal effect of general alcohol intake and pathological drinking behaviors on psychiatric disorders, alcohol\u2010associated DNA methylation on gene expression and psychiatric disorders, and gene expression on psychiatric disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Two\u2010sample design Mendelian randomization (MR) analysis. Various sensitivity and validation analyses, including colocalization analysis, were conducted to test the robustness of the results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Genome\u2010wide association study (GWAS) data mainly from GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetics of DNA Methylation Consortium (GoDMC) and Psychiatric Genomics Consortium (PGC) with European ancestry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>The GWAS summary data on general alcohol intake (drinks per week, <jats:italic>n<\/jats:italic>\u2009=\u2009941\u2009280), pathological drinking behaviors (including alcohol use disorder [AUD, <jats:italic>n<\/jats:italic>\u2009=\u2009313\u2009959] and problematic alcohol use [PAU, <jats:italic>n<\/jats:italic>\u2009=\u2009435\u2009563]) and psychiatric disorders (including schizophrenia, major depressive disorder and bipolar disorder, <jats:italic>n<\/jats:italic>\u2009=\u200951\u2009710\u2013500\u2009199) were included. Alcohol\u2010related DNA methylation CpG sites (<jats:italic>n<\/jats:italic>\u2009=\u20099643) and mQTL data from blood (<jats:italic>n<\/jats:italic>\u2009=\u200927\u2009750) and brain (<jats:italic>n<\/jats:italic>\u2009=\u20091160), BrainMeta v2 and GTEx V8 eQTL summary data (<jats:italic>n<\/jats:italic>\u2009=\u200973\u20132865) were also included.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements<\/jats:title><jats:p>Genetic variants were selected as instrumental variables for exposures, including drinks per week, AUD, PAU, alcohol\u2010related DNA methylation CpG sites (mQTL) and genes selected (eQTL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>Pathological drinking behaviors were associated with an increased risk of psychiatric disorders after removing outliers or controlling for alcohol consumption. MR analysis identified 10 alcohol\u2010related CpG sites with colocalization evidence that were causally associated with psychiatric disorders (<jats:italic>P<\/jats:italic>\u2009=\u20091.65\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>\u20137.52\u2009\u00d7\u200910<jats:sup>\u221222<\/jats:sup>). Furthermore, the expression of genes (<jats:italic>RERE<\/jats:italic>, <jats:italic>PTK6<\/jats:italic>, <jats:italic>GATAD2B<\/jats:italic>, <jats:italic>COG8<\/jats:italic>, <jats:italic>PDF<\/jats:italic> and <jats:italic>GAS5<\/jats:italic>) mapped to these CpG sites in the brain, led by the cortex, were significantly associated with psychiatric disorders (<jats:italic>P<\/jats:italic>\u2009=\u20091.19\u2009\u00d7\u200910<jats:sup>\u22122<\/jats:sup>\u20133.51\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Pathological drinking behavior and alcohol\u2010related DNA methylation appear to have a causal effect on psychiatric disorders. The expression of genes regulated by the alcohol\u2010related DNA methylation sites may underpin this association.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.16465","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T08:11:07Z","timestamp":1711354267000},"page":"1226-1237","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Alcohol drinking, DNA methylation and psychiatric disorders: A multi\u2010omics Mendelian randomization study to investigate causal pathways"],"prefix":"10.1111","volume":"119","author":[{"given":"Xiaoqiang","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital Zhejiang 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Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"Research Center for Air Pollution and Health Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongli","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 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