目的:酒精相关的DNA甲基化是否对精神疾病有因果关系尚未研究。此外,一直缺乏对饮酒与精神疾病之间的因果关系和潜在机制的全面调查.本研究旨在评估一般饮酒和病理性饮酒行为对精神疾病的因果关系。酒精相关的DNA甲基化对基因表达和精神疾病,和精神疾病的基因表达。
方法:双样本设计孟德尔随机化(MR)分析。各种敏感性和验证分析,包括共定位分析,进行了测试,以测试结果的稳健性。
方法:全基因组关联研究(GWAS)数据主要来自GWAS和酒精和尼古丁使用测序联盟(GSCAN),具有欧洲血统的DNA甲基化联盟(GoDMC)和精神病学基因组学联盟(PGC)的遗传学。
方法:关于一般酒精摄入量的GWAS汇总数据(每周饮料,n=941280),病理性饮酒行为(包括饮酒障碍[AUD,n=313959]和有问题的酒精使用[PAU,n=435563])和精神疾病(包括精神分裂症,抑郁症和双相情感障碍,n=51710-500199)。酒精相关的DNA甲基化CpG位点(n=9643)和来自血液(n=27750)和大脑(n=1160)的mQTL数据,还包括BrainMetav2和GTExV8eQTL汇总数据(n=73-2865)。
方法:选择遗传变异作为暴露的工具变量,包括每周的饮料,AUD,PAU,与酒精相关的DNA甲基化CpG位点(mQTL)和选择的基因(eQTL)。
结果:病理性饮酒行为与排除异常值或控制饮酒后精神疾病风险增加相关。MR分析确定了10个与酒精相关的CpG位点,这些位点具有与精神疾病有因果关系的共定位证据(P=1.65×10-4-7.52×10-22)。此外,基因的表达(RERE,PTK6,GATAD2B,COG8,PDF和GAS5)映射到大脑中的这些CpG位点,由大脑皮层领导,与精神疾病显著相关(P=1.19×10-2-3.51×10-7)。
结论:病理性饮酒行为和酒精相关的DNA甲基化似乎对精神疾病有因果关系。由酒精相关的DNA甲基化位点调节的基因的表达可能是这种关联的基础。
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 × 10-4-7.52 × 10-22). 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 × 10-2-3.51 × 10-7).
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.