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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. [ABSTRACT FROM AUTHOR]

Introduction The number of smokers worldwide increased greatly during the past decades and reached 1.14 billion in 2019, becoming a leading risk factor for human health. Tobacco smoking has wide effects on human genetics, epigenetics, transcriptome, and gut microbiome. Although many studies have revealed effects of smoking on host transcriptome, research on the relationship between smoking, host gene expression, and the gut microbiome is limited. Aims and Methods We first explored transcriptome and metagenome profile differences between smokers and nonsmokers. To evaluate the relationship between host gene expression and gut microbiome, we then applied bidirectional mediation analysis to infer causal relationships between smoking, gene expression, and gut microbes. Results Metagenome and transcriptome analyses revealed 71 differential species and 324 differential expressed genes between smokers and nonsmokers. With smoking as an exposure variable, we identified 272 significant causal relationships between gene expression and gut microbes, among which there were 247 genes that mediate the effect of smoking on gut microbes. Pathway-based enrichment analysis showed that these genes were significantly enriched in heme metabolic pathway, which mainly mediated the changes of Bacteroides finegoldii and Lachnospiraceae bacterium 9_1_43BFAA. Additionally, by performing metabolome data analysis in the Integrated Human Microbiome Project (iHMP) database, we verified the correlation between the intermediate products of the heme metabolism pathway (porphobilinogen, bilirubin, and biliverdin) and gut microbiome. Conclusions By investigating the bidirectional interaction between smoking-related host gene expression and gut microbes, this study provided evidence for the mediation of smoking on gut microbes through co-involvement or interaction of heme metabolism. Implications By comparing the metagenome and transcriptome sequencing profiles between 34 smokers and 33 age- and gender-matched nonsmokers, we are the first to reveal causal relationships among tobacco smoking, host gene expression, and gut microbes. These findings offer insight into how smoking affects gut microbes through host gene expression and metabolism, which highlights the importance of heme metabolism in modulating the effects of smoking on gut microbiome. [ABSTRACT FROM AUTHOR]

To build capacity and collaborative research for future cross-national studies in the Asian and Pacific Islander (API) region, priority research topics were identified and discussed at the April 2013 Conference to Promote Global Health in Taipei. These topics included (1) Neuroscience on HIV/HCV and amphetamine-type stimulants (ATS), led by Drs. Linda Chang, Gene-Jack Wang, and Betty Tai; (2) ATS and mental health disorders, led by Drs. Richard Rawson and Wilson Compton; and (3) HIV/HCV transmission and social networks, led by Drs. Steven Shoptaw and Jacques Normand. Potential genetic studies spanning these topical areas as well as the importance of smoking cessation were further discussed, led by Dr. Ming Li. Additional priority research topics were also identified: (4) Drug use prevention, and (5) Family involvement to improve treatment adherence and recovery. Workgroups on these topics will be formed to prioritize research questions within the respective topical area and to determine the next steps. The ultimate goal of these workgroups is to stimulate collaboration that will eventually lead to research studies addressing critical issues related to the rising substance abuse and HIV infection rates in many Asian countries and, at the same time, to advance the scientific knowledge of substance abuse and HIV infection.

Abnormal myelin gene expression in the central nervous system (CNS) is associated with many mental illnesses, including psychiatric disorders and drug addiction. We have previously shown that prenatal exposure to nicotine, the major psychoactive component in cigarette smoke, alters myelin gene expression in the CNS of adolescent rats. To examine whether this effect is specific for adolescents, we examined myelin gene expression in the CNS of juveniles and adults. Pregnant Sprague-Dawley rats were treated with nicotine (3 mg/kg/day; GN) or saline (GS) via osmotic mini pumps from gestational days 4-18. Both male and female offspring were sacrificed at postnatal day P20-21 (juveniles), P35-36 (adolescents), or P59-60 (adults). Three limbic brain regions, the prefrontal cortex (PFC), caudate putamen (CPu), and nucleus accumbens (NAc), were dissected. The expression of genes encoding major myelin components was evaluated using quantitative RT-PCR. We found that GN altered myelin gene expression in juveniles with brain region and sex differences. The pattern of alteration was different from that observed in adolescents. Although these genes were expressed normally in male adults, we observed decreased expression in GN-treated female adults, especially in the CPu. Thus, GN altered myelin gene expression throughout postnatal development and adulthood. The effect on adolescents was quite different from that at other ages, which correlated with the unique symptoms of many psychiatric disorders during adolescence.