Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target

Abstract

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10−8) with the five leading probes located in SLC7A11 (p = 7.75 × 10−108), JDP2 (p = 1.44 × 10−56), GAS5 (p = 2.71 × 10−47), TRA2B (p = 3.54 × 10−42), and SLC43A1 (p = 1.18 × 10−40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer’s disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10−09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10−38 and p = 5.41 × 10−14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10−17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10−4), increased liver function enzymes (GGT (p = 1.03 × 10−21), ALT (p = 1.29 × 10−6), and AST (p = 1.97 × 10−8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

“…Xc-is the cystine-glutamate antiporter encoded by SLC7A11, which facilitates glutamatergic transmission, oxidative stress defence and microglial response in the brain 42,43 and is a target for the neurodegeneration-associated environmental neurotoxin β-methylamino-L-alanine 41 . Analyses in the wider Generation Scotland cohort suggests that cg06690548 is a site associated with alcohol consumption 44 . The proteins associated with cg06690548 in the subset of this cohort that we assessed (ACY1, SCUBE1 and RBP5) have known links to liver function [45][46][47] .…”

Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging

“…DNAmTL is also an important epigenetic biomarker, which captures additional aspects of molecular aging, in particular the link between cell replication and age-related diseases. Importantly, the 140 CpGs we used to predict DNAmTL did not overlap with any previously identified alcohol-related CpGs (2504 CpGs for alcohol consumption [ 60 ], 96 for AUD [ 29 ]), reducing the likelihood that alcohol might have a confounding influence on measuring methylation-based TL.…”

The Interplay of Epigenetic, Genetic, and Traditional Risk Factors on Blood Pressure: Findings from the Health and Retirement Study

“…Solute carrier family 7 member 11 ( SLC7A11 ) is a major regulator of metabolic reprogramming including nutrient dependency and intracellular redox balance. Increased expression SLC7A11 was associated with poor prognosis in cancer [ 46 ], alcohol use disorders [ 47 ], and increased BP [ 6 ]. DNA methylation at cg00574958 was associated with decreased expression of UNC93B1 and increased expression of CPT1A.…”