Alcohol drinking, DNA methylation and psychiatric disorders: A multi-omics Mendelian randomization study to investigate causal pathways

IF 5.2 1区医学 Q1 PSYCHIATRY

Addiction Pub Date : 2024-03-25 DOI:10.1111/add.16465

Xiaoqiang Shi, Meng Li, Jianhua Yao, Ming D. Li, Zhongli Yang

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引用次数: 0

Abstract

Background and aims

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.

Design

Two-sample design Mendelian randomization (MR) analysis. Various sensitivity and validation analyses, including colocalization analysis, were conducted to test the robustness of the results.

Setting

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.

Participants

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.

Measurements

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).

Findings

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).

Conclusions

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.

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饮酒、DNA 甲基化与精神疾病：多组学孟德尔随机化研究探究因果关系。

背景和目的：与酒精相关的 DNA 甲基化是否对精神疾病有因果影响，目前尚未有研究。此外，关于饮酒与精神疾病之间的因果关系和内在机制也缺乏全面的调查。本研究旨在评估一般酒精摄入和病态饮酒行为对精神障碍的因果效应、酒精相关DNA甲基化对基因表达和精神障碍的因果效应以及基因表达对精神障碍的因果效应：设计：双样本设计孟德尔随机（MR）分析。进行了各种敏感性和验证分析，包括共定位分析，以检验结果的稳健性：全基因组关联研究（GWAS）数据主要来自欧洲血统的酒精和尼古丁使用GWAS和测序联盟（GSCAN）、DNA甲基化遗传学联盟（GoDMC）和精神病基因组学联盟（PGC）：纳入了一般酒精摄入量（每周饮酒量，n = 941 280）、病态饮酒行为（包括酒精使用障碍[AUD，n = 313 959]和问题酒精使用[PAU，n = 435 563]）和精神障碍（包括精神分裂症、重度抑郁障碍和躁狂症，n = 51 710-500 199）的 GWAS 总结数据。此外，还纳入了与酒精相关的 DNA 甲基化 CpG 位点（n = 9643）以及来自血液（n = 27 750）和大脑（n = 1160）的 mQTL 数据、BrainMeta v2 和 GTEx V8 eQTL 摘要数据（n = 73-2865）：选择基因变异作为暴露的工具变量，包括每周饮酒量、AUD、PAU、酒精相关DNA甲基化CpG位点（mQTL）和所选基因（eQTL）：研究结果：去除异常值或控制饮酒量后，病态饮酒行为与精神障碍风险的增加有关。MR分析发现了10个与酒精相关的CpG位点，这些位点具有共定位证据，与精神障碍有因果关系（P = 1.65 × 10-4-7.52 × 10-22）。此外，映射到这些 CpG 位点的基因（RERE、PTK6、GATAD2B、COG8、PDF 和 GAS5）在大脑皮层的表达与精神障碍显著相关（P = 1.19 × 10-2-3.51 × 10-7）：结论：病态饮酒行为和酒精相关 DNA 甲基化似乎对精神疾病有因果关系。与酒精相关的 DNA 甲基化位点所调控的基因表达可能是这种关联的基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Addiction 医学-精神病学

CiteScore

10.80

自引率

6.70%

发文量

319

审稿时长

3 months

期刊介绍： Addiction publishes peer-reviewed research reports on pharmacological and behavioural addictions, bringing together research conducted within many different disciplines. Its goal is to serve international and interdisciplinary scientific and clinical communication, to strengthen links between science and policy, and to stimulate and enhance the quality of debate. We seek submissions that are not only technically competent but are also original and contain information or ideas of fresh interest to our international readership. We seek to serve low- and middle-income (LAMI) countries as well as more economically developed countries. Addiction’s scope spans human experimental, epidemiological, social science, historical, clinical and policy research relating to addiction, primarily but not exclusively in the areas of psychoactive substance use and/or gambling. In addition to original research, the journal features editorials, commentaries, reviews, letters, and book reviews.