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, China.
Joint Institute of Tobacco and Health, Kunming, Yunnan, China.
Addiction. 2024 Jul;119(7):1226-1237. doi: 10.1111/add.16465. Epub 2024 Mar 25.
Whether alcohol-related 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-associated DNA methylation on gene expression and psychiatric disorders, and gene expression on psychiatric disorders.
Two-sample design Mendelian randomization (MR) analysis. Various sensitivity and validation analyses, including colocalization analysis, were conducted to test the robustness of the results.
Genome-wide 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.
The GWAS summary data on general alcohol intake (drinks per week, n = 941 280), pathological drinking behaviors (including alcohol use disorder [AUD, n = 313 959] and problematic alcohol use [PAU, n = 435 563]) and psychiatric disorders (including schizophrenia, major depressive disorder and bipolar disorder, n = 51 710-500 199) were included. Alcohol-related DNA methylation CpG sites (n = 9643) and mQTL data from blood (n = 27 750) and brain (n = 1160), BrainMeta v2 and GTEx V8 eQTL summary data (n = 73-2865) were also included.
Genetic variants were selected as instrumental variables for exposures, including drinks per week, AUD, PAU, alcohol-related DNA methylation CpG sites (mQTL) and genes selected (eQTL).
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-related CpG sites with colocalization evidence that were causally associated with psychiatric disorders (P = 1.65 × 10-7.52 × 10). Furthermore, the expression of genes (RERE, PTK6, GATAD2B, COG8, PDF and GAS5) mapped to these CpG sites in the brain, led by the cortex, were significantly associated with psychiatric disorders (P = 1.19 × 10-3.51 × 10).
Pathological drinking behavior and alcohol-related DNA methylation appear to have a causal effect on psychiatric disorders. The expression of genes regulated by the alcohol-related DNA methylation sites may underpin this association.
酒精相关的 DNA 甲基化是否对精神疾病有因果关系尚未得到研究。此外，缺乏对饮酒和精神疾病之间的因果关系和潜在机制的全面研究。本研究旨在评估一般饮酒量和病理性饮酒行为对精神疾病、酒精相关 DNA 甲基化对基因表达和精神疾病以及基因表达对精神疾病的因果影响。
双样本设计孟德尔随机化（MR）分析。进行了各种敏感性和验证分析，包括共定位分析，以测试结果的稳健性。
全基因组关联研究（GWAS）数据主要来自 GWAS 和酒精与尼古丁使用的测序联盟（GSCAN）、DNA 甲基化遗传联盟（GoDMC）和精神疾病基因组学联盟（PGC），具有欧洲血统。
纳入了一般饮酒量（每周饮酒量，n=941280）、病理性饮酒行为（包括酒精使用障碍 [AUD，n=313959] 和问题性饮酒 [PAU，n=435563]）和精神疾病（包括精神分裂症、重度抑郁症和双相情感障碍，n=51710-500199）的 GWAS 汇总数据。还纳入了与酒精相关的 DNA 甲基化 CpG 位点（n=9643）和血液（n=27750）和大脑（n=1160）中的 mQTL 数据、BrainMeta v2 和 GTEx V8 eQTL 汇总数据（n=73-2865）。
选择遗传变异作为暴露的工具变量，包括每周饮酒量、AUD、PAU、与酒精相关的 DNA 甲基化 CpG 位点（mQTL）和选择的基因（eQTL）。
病理性饮酒行为与精神疾病风险增加相关，去除异常值或控制饮酒量后仍如此。MR 分析确定了 10 个与酒精相关的 CpG 位点，具有共定位证据，与精神疾病有因果关系（P=1.65×10-7.52×10）。此外，映射到这些 CpG 位点的基因（RERE、PTK6、GATAD2B、COG8、PDF 和 GAS5）的表达在大脑中，以皮质为主，与精神疾病显著相关（P=1.19×10-3.51×10）。
病理性饮酒行为和与酒精相关的 DNA 甲基化似乎对精神疾病有因果关系。受与酒精相关的 DNA 甲基化位点调节的基因的表达可能是这种关联的基础。
